KR101331768B1 - Heterocyclic modulators of ATP-binding cassette transporters - Google Patents

Abstract

Compounds of the invention and pharmaceutically acceptable compositions thereof are useful as modulators of ATP-binding cassette (“ABC)” transporters or fragments thereof, including cystic fibroma transmembrane conduction regulators (“CFTR”). The present invention also relates to a method of treating ABC transporter mediated diseases using the compounds of the present invention.

ABC transporters, cystic fibrosis, modulators, diarrhea.

Description

Heterocyclic modulators of ATP-binding cassette transporters

Cross Reference of Related Application

This application is directed to U.S. Provisional Patent Application No. 60 / 734,506, filed Nov. 8, 2005, U.S. Provisional Patent Application No. 60 / 754,086, filed Dec. 27, 2005, and US, filed May 22, 2006. 35 USC of Provisional Patent Application 60 / 802,458 Claims under § 119, the entire contents of each of the above applications being incorporated herein by reference.

The present invention relates to modulators of ATP-binding cassette (“ABC)” transporters or fragments thereof, comprising the cystic fibroma transmembrane conduction regulator (“CFTR”), compositions thereof, and methods of using the same. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

ABC transporters are a class of membrane transporter proteins that regulate the transport of anions as well as a wide variety of pharmacological agents, potentially toxic agents and bioforeigns. ABC transporters are homogeneous membrane proteins that bind and use adenosine triphosphate (ATP) of cells for their specific activity. Some of these transporters have been found as multi-drug resistant proteins (such as MDR1-P glycoproteins or multi-drug resistant proteins, MRP1), which defend malignant cancer cells against chemotherapeutic agents. So far, 48 ABC transporters have been identified and grouped into seven classes based on their sequence identification and function.

ABC transporters regulate various important physiological roles in the body and provide protection against harmful environmental compounds. To this end, this represents an important potential drug target for the treatment of diseases associated with defects of the transporter, prevention of drug transport outside the target cell, and the mediation of other diseases in which modulation of ABC transporter activity may be advantageous.

One member of the class of ABC transporters generally associated with disease is the cAMP / ATP mediated anion channel, CFTR. CFTR is expressed in a variety of cell types, including uptake and secretory epithelial cells, where they regulate the activity of other ion channels and proteins as well as anion flux across the membrane. In epithelial cells, the normal function of CFTR is important for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR consists of about 1480 amino acids encoding a protein consisting of a series repeat of the transmembrane domain, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by large, polar regulatory (R) -domains with multiple phosphorylation sites that regulate channel activity and cell trafficking.

Gene encoding CFTR has been identified and sequenced. Gregory, R. J. et al. (1990) Nature 347: 382-386; Rich, D. P. et al. (1990) Nature 347: 358-362), (Riordan, JR et al. (1989) Science 245: 1066-1073.) Mutations in CFTR due to genetic defects result in cystic fibrosis, the most common lethal genetic disease in humans (" CF "). Cystic fibroids occur in the United States every year in about 1 in 2,500 infants. Of the general US population, up to 10 million people have a single copy of the defective gene without apparent adverse effects. In contrast, CF Individuals with two copies of related genes suffer from lethal weakening of CF, including chronic lung disease.

In patients with cystic fibrosis, CFTR mutations expressed endogenously in the respiratory epithelium induce reduced apical anion secretion resulting in an imbalance in ion and fluid transport. The resulting reduced anion transport, together with enhanced mucus accumulation in the lung, causes microbial infections and ultimately death of CF patients. In addition to respiratory diseases, CF patients usually suffer from gastrointestinal problems and dysfunction, leading to death if not treated. In addition, the majority of males with cystic fibrosis are infertile and the fertility decreases among females with cystic fibrosis. In contrast to the serious action of the two copies of the CF-related gene, individuals with a single copy of the CF-related gene show increased resistance to dehydration due to cholera and diarrhea, which accounts for the relatively high frequency of CF genes in the population. do.

Sequence analysis of the CFTR gene of the CF chromosome revealed various disease-causing mutations (Cutting, GR et al. (1990) Nature 346: 366-369; Dean, M. et al. (1990) Cell 61: 863: 870; and Kerem, BS. Et al. (1989) Science 245: 1073-1080; Kerem, BS et al. (1990) Proc. Natl. Acad. Sci. USA 87: 8447-8451). To date, disease-causing mutations in more than 1000 CF genes have been identified (http://www.genet.sickkids.on.ca/cftr/). The most prevalent mutation is the deletion of phenylalanine at position 508 of the CFTR amino acid sequence, commonly referred to as ΔF508-CFTR. This mutation occurs in about 70% of the causes of cystic fibrosis and is associated with serious disease.

The deletion of residue 508 of ΔF508-CFTR prevents the initial protein from folding correctly. This prevents the mutant protein from entering the ER and induces traffic to the plasma membrane. As a result, the number of channels present in the membrane is much less than that observed in cells expressing wild type CFTR. In addition to impaired trafficking, mutations result in defective channel gating. In addition, the reduced number of channels of membrane and defect gating leads to reduced anion transport across the epithelium leading to defective ion and fluid transport (see Quinton, PM (1990), FASEB J. 4: 2709-). 2727). However, studies have shown that the reduced number of ΔF508-CFTR of membranes is functional, albeit less than wild type CFTR (Dalemans et al. (1991), Nature Lond. 354: 526-528; Denning et al. , supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to ΔF508-CFTR, other disease-causing mutations of CFTR that cause defective trafficking, synthesis and / or channel gating may be up or down regulated to alter anion secretion and modify disease progression and / or severity.

Although CFTR transports various molecules in addition to anions, this role (anion transport) represents one element of an important mechanism of transport of ions and water across the epithelium. Includes a / K ⁺ cotransporter, Na ⁺ -K ⁺ -ATPase pump and the basolateral membrane K ⁺ channels ^- other factors is serving to absorb the chloride into the cell, epithelial Na ⁺ channel, ENaC, Na ⁺ / 2Cl .

These elements together work to achieve direct transport across the epithelium through its selective expression and location in the cell. Chloride uptake is caused by the cooperative activity of ENaC and CFTR present on the tip membrane and the Na ⁺ -K ⁺ -ATPase pump and Cl- channel expressed on the basal surface of the cell. The second active transport of chloride from the bore side leads to the accumulation of intracellular chloride, which then passively leaves the cell through the Cl ⁻ channel leading to vector transport. Basolateral surface of the Na ⁺ / 2Cl ^- / K ⁺ array of cotransporter, Na ⁺ -K ⁺ -ATPase pump and the basolateral membrane K ⁺ channels and the side aperture CFTR will be helpful in the secretion of chloride via CFTR the side aperture . Since water is largely not actively active in itself, its flow across the epithelium depends on the small epithelial pain and osmotic pressure gradients generated by the bulk flow of sodium and chloride.

In addition to cystic fibrosis, modulation of CFTR activity may be beneficial for other diseases not directly caused by mutations in CFTR, such as secretory diseases and other protein folding diseases mediated by CFTR. These diseases include, but are not limited to, chronic obstructive pulmonary disease (COPD), dry eye disease and Sjogren's syndrome.

COPD is characterized by airflow limitations that are not progressive or fully reversible. Airflow limits are due to mucus oversecretion, air species and bronchiolitis. Activators of mutant or wild type CFTR provide common treatment of mucus hypersecretion and impaired mucosal cilia in COPD. Specifically, it is possible to hydrate mucus and optimized ciliary viscosity by increasing anion secretion across CFTR to facilitate fluid transport to the airway surface liquid. This will lead to enhanced mucosal cilia and reduced symptoms associated with COPD. Dry eye disease is characterized by reduced tear production and abnormal tear film lipid, protein and mucin profiles. There are a number of causes of dry eye, some of which include age, LASIK, arthritis, medication, chemical / thermal burns, allergies and diseases such as cystic fibrosis and Surren syndrome. Increased anion secretion through CFTR will enhance corneal hydration by enhancing fluid transport from the corneal epithelial cells and glands surrounding the eye. This will help to alleviate the symptoms associated with dry eye disease. Surren's syndrome is an autoimmune disease in which the immune system attacks moisture producing lines through the body, including the eyes, mouth, skin, respiratory tissue, liver, vagina and intestines. Symptoms include dry eye, mouth and vaginal dryness as well as lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis and polymyositis / skin myositis. Defective protein trafficking is believed to cause disease, which limits treatment options. Modulators of CFTR activity may help to hydrate various organs suffering from the disease and to elevate related symptoms.

As discussed above, it is believed that the deletion of the 508 residues of ΔF508-CFTR prevents the initial protein from folding correctly, preventing these mutant proteins from entering the ER and generating traffic to the plasma membrane. As a result, insufficient amount of mature protein is present in the plasma membrane, and chloride transport in epithelial tissue is significantly reduced. In fact, this intracellular phenomenon of defective ER treatment of ABC transporters by the ER machinery has been shown to be a fundamental basis for CF disease as well as a wide variety of other isolated genetic diseases. Two ways in which the ER machinery can malfunction are to induce degradation due to loss of coupling to the ER propagation of the protein or to accumulate the ER of such a defective / dysfunctional protein. Aridor M, et al . Nature Med., 5 (7), pp 745-751 (1999); Shastry, BS, et al ., Neurochem. International, 43 , pp 1-7 (2003); Rutishauser, J., et al ., Swiss Med Wkly, 132 , pp 211-222 (2002); Morello, JP et al ., TIPS, 21 , pp. 466-469 (2000); Bross P., et al ., Human Mut., 14 , pp. 186-198 (1999). Diseases associated with the first class of ER dysfunction include cystic fibrosis (due to misfolded ΔF508-CFTR as discussed above), hereditary emphysema (due to a1-antitrypsin; not the Piz variant), hereditary hemochromatosis, coagulation-fibrosis Lytic deficiency, eg, protein C deficiency, type 1 hereditary angioedema, lipid processing deficiency, eg, familial hypercholesterolemia, type 1 kilomicronemia, mubetalipoproteinemia, lysosomal storage disease, for example For example, I-cell disease / pseudo-Huller disease, mucopolysaccharide (due to lysosomal processing enzymes), Sandhof / Tay-Sachs (due to β-hexosaminidase), type II Krigler-Nazar (due to UDP-glucuronyl-sialic-transferase), multi-occurrence endocrine disorders / hyperinsulinemia, diabetes (due to insulin receptors), laron dwarfism (due to growth hormone receptors) , Myeloperoxidase deficiency, primary parathyroid Hypoxia (due to preproparatiroid hormones), melanoma (due to tyrothiasis). Diseases associated with the latter class of ER dysfunction include type 1 glycolytic CDG, hereditary emphysema (due to α1 antitrypsin (Piz strain)), congenital hyperthyroidism, incomplete osteopenia (types I, II, IV pro) Collagen), hereditary hypofibrinemia (due to fibrinogen), ACT deficiency (due to α1-antichymotrypsin), diabetes insipidus (DI), and neurophagy diabetes insipidus (due to vasopressin hormone / V2-receptor) , Identity diabetes insipidus (due to Aquaporin II), Sharco-Maritus syndrome (due to peripheral myelin protein 22), Perijaeus-Mertzvacher's disease, neurodegenerative diseases such as Alzheimer's disease (βAPP And presenilin), Parkinson's disease, amyotrophic lateral sclerosis, progressive nuclear palsy, Pick's disease, several polyglutamine neurological disorders, such as Huntington's disease, type I spinal cord ataxia, spinal and bulbous muscular dystrophy, dental nucleus Red-nuclear wall As well as upper and lower nucleus atrophy and myotonic dystrophy, cavernous encephalopathy, such as hereditary Cropfeld-Jakob disease (due to prion protein processing defects), Fabry's disease (due to lysosomal α-galactosidase A) And Straussler-Shinker Syndrome (due to Prp treatment defects).

In addition to upregulating CFTR activity, reducing anion secretion by CFTR modulators may be beneficial for the treatment of secretory diarrhea, in which epithelial water transport is greatly increased due to secretagogue activated chloride transport. The mechanism involves the elevation of cAMP and the stimulation of CFTR.

Although there are many causes of diarrhea, the main consequences of diarrheal disease caused by excessive chloride transport are common to all and include dehydration, acidosis, impaired growth and death.

Acute and chronic diarrhea represent major medical problems in many parts of the world. Diarrhea is an important factor in malnutrition and the leading cause of death for infants under five (5,000,000 deaths per year).

Secretory diarrhea is also a dangerous condition in patients with acquired immune deficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD). Sixteen million travelers experience diarrhea each year, from industrialized countries to developing countries, and the severity and number of cases of diarrhea vary by travel country and region.

Barn animals and pets, also known as scores, such as cattle, pigs, horses, sheep, goats, cats, and dog diarrhea are also major causes of death in these animals. Diarrhea can occur from any major metastasis, such as a response to various bacterial or viral infections, as well as weaning and physical migration, and generally occurs within the first few hours of animal life.

The bacterium that causes most common diarrhea is enterrotoxogenic E-coli (ETEC) with the K99 pilus antigen. Common viral causes of diarrhea include rotavirus and coronavirus. Other infectious agents include, in particular, cryptosporidium, giardia lamblia and salmonella.

Symptoms of rotavirus infection include watery side, dehydration and weakness. Coronaviruses cause more serious diseases in newborns and have a higher mortality rate than rotavirus infections. However, often young animals can be infected with more than one virus or combination of viruses and bacterial microorganisms at one time. This greatly increases the severity of the disease.

Thus, there is a need for modulators of ABC transporter activity and compositions thereof that can be used to modulate the activity of ABC transporters in mammalian cell membranes.

There is a need for methods of treating ABC transporter mediated diseases using such modulators of ABC transporter activity.

There is a need for a method of modulating ABC transporter activity in mammalian ex vivo cell membranes.

There is a need for modulators of CFTR activity that can be used to modulate the activity of CFTR in mammalian cell membranes.

There is a need for methods of treating CFTR mediated diseases using such modulators of CFTR activity.

There is a need for a method of modulating CFTR activity in mammalian ex vivo cell membranes.

Summary of the Invention

It has now been found that the compounds of the invention and pharmaceutically acceptable compositions thereof are useful as modulators of ABC transporter activity. The compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In the above formula (I)

R ₁ , R ₂ , R ₃ , R ' ₃ , R ₄ and n are as defined herein.

The compounds and pharmaceutically acceptable compositions include, but are not limited to cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolytic deficiency, such as protein C deficiency, type 1 hereditary angioedema, lipid treatment Deficiency, eg, familial hypercholesterolemia, type 1 kilomicronemia, mubetalipoproteinemia, lysosomal storage diseases, eg, I-cell disease / caustic huler disease, mucopolysaccharide, sandhof / tei Sarks, type II Krigler-Nazar, multi-occurrence endocrine disorders / hyperinsulinemia, diabetes mellitus, laron dwarfism, myeloperoxidase deficiency, primary parathyroidism, melanoma, type 1 glycanogenic CDG, hereditary emphysema, congenital Hyperthyroidism, incomplete osteocytosis, hereditary hypofibrosis, ACT deficiency, diabetes insipidus (DI), neurophagy insipidus, identity insipidus, Sharco-Maritus syndrome, Perizaeus-mer Barcher's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive nuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington's disease, type I spinal cord ataxia, spine And spongiform encephalopathy such as hereditary Croissant-Jacob disease, Fabry's disease, Straussler-Shinker syndrome, COPD, dry eye syndrome and extraocular bulbs, as well as bulbous muscular dystrophy, plaque nucleus cholangiotrophic atrophy and myotonic dystrophy It is useful for treating or alleviating the severity of various diseases, disorders or conditions, including Green's disease.

Justice

As used herein, the following definitions apply unless otherwise indicated.

As used herein, the term “ABC transporter” is an ABC transporter protein or fragment thereof comprising one or more binding domains, wherein the protein or fragment thereof is present in vivo or in vitro. As used herein, the term "binding domain" refers to a domain on the ABC transporter capable of binding a modulator. See, eg, Hwang, TC et al. , J. Gen. Physiol. (1998): 111 (3), 477-90.

As used herein, the term "CFTR" refers to a cystic fibrosis transmembrane conductivity modulator or a mutation thereof that may have modulator activity, including but not limited to ΔF508 CFTR and G551D CFTR [For CFTR mutations, For example, see: http://www.genet.sickkids.on.ca/cftr/).

As used herein, the term “adjustment” means, for example, an increase or decrease in activity by a measurable amount. Compounds that modulate ABC transporter activity, such as CFTR activity by increasing the activity of the ABC transporter, such as the CFTR anion channel, are called agonists. Compounds that modulate ABC transporter activity, such as CFTR activity by reducing the activity of ABC transporters, such as CFTR anion channels, are termed antagonists. Agonists interact with ABC transporters such as CFTR anion channels to increase the ability of the receptor to convert intracellular signals in response to endogenous ligand binding. Antagonists interact with ABC transporters, eg, CFTR, and compete with endogenous ligand (s) or substrate (s) for binding site (s) on the receptor, thereby causing the receptor to respond to endogenous ligand binding to signal intracellular signals. Reduces the ability to convert

The phrase “treat or reduce the severity of ABC transporter mediated disease” is not directly induced by ABC transporter and / or CFTR anion channel activity and treatment for diseases directly induced by ABC transporter and / or CFTR activity. Not alleviation of disease symptoms. Examples of diseases in which symptoms may be affected by ABC transporter and / or CFTR activity include, but are not limited to, cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolytic deficiency, eg, protein C. Deficiency, type 1 hereditary angioedema, lipid processing deficiency, e.g. familial hypercholesterolemia, type 1 kilomicronemia, mubetalipoproteinemia, lysosomal storage disease, e.g. I-cell disease / caustic hull Leukemia, Mucopolysaccharide, Sandhof / Tey-Sarks, Type II Krigler-Nazar, Multioccurrence Endocrine Disorders / Insulinemia, Diabetes, Laron Dwarfism, Myeloperoxidase Deficiency, Primary Parathyroidism, Melanoma, 1 Glycolytic CDG, Hereditary Emphysema, Congenital Hypothyroidism, Incomplete Osteosynthesis, Hereditary Hypofibrosis, ACT Deficiency, Insipidus (DI), Neurophagy Insipidosis, Identity Insipidosis, Charco-Maritus Group, Perijaeus-Mertzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive nuclear palsy, pick disease, some polyglutamine nervous system disorders such as Huntington Disease, type I spinal cord ataxia, spinal and bulbar muscular atrophy, spontaneous nucleus cholangiotrophic atrophy and myotonic dystrophy, as well as cavernous encephalopathy such as hereditary Cropfeld-Jacob disease, Fabry's disease, Straussler-Shine Kerr syndrome, COPD, dry eye, and Sjogren's disease.

For the purposes of the present invention, chemical elements are identified according to the Periodic Table of Elements (CAS version, Handbook of Chemistry and Physics, 75th Ed.). In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausolito: 1999; March's Advanced Organic Chemistry, 5th Ed., Ed .: Smith, M.B. And March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

For the purposes of the present invention, chemical elements are identified according to the Periodic Table of Elements (CAS version, Handbook of Chemistry and Physics, 75th Ed.). In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausolito: 1999; March's Advanced Organic Chemistry, 5th Ed., Ed .: Smith, M.B. And March, J., John Wiley & Sons, New York: 2001.

As used herein, the term "aliphatic" includes the terms alkyl, alkenyl, alkynyl, each of which is optionally substituted as described below.

As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms (eg, 1 to 6 or 1 to 4). Alkyl groups may be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, n-heptyl or 2-ethylhexyl. Alkyl groups are halo, alicyclic [e.g. cycloalkyl or cycloalkenyl], heteroalicyclic [e.g. heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [ Examples: (aliphatic) carbonyl, (alicyclic) carbonyl, or (heterocyclic) carbonyl], nitro, cyano, amido [e.g. (Cycloalkylalkyl) carbonylamino, arylcarbonylamino, ar Alkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino], amino [e.g. Aliphatic amino, alicyclic amino, or Heteroalicyclic amino], sulfonyl [e.g. aliphatic sulfonyl], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphatic oxy, heteroalicyclic Oxy, aryloxy, heteroaryloxy, aralkyl jade , Heteroaryl, alkoxy, alkoxycarbonyl, It may be substituted (ie, optionally substituted) with one or more substituents, such as alkylcarbonyloxy, or hydroxy. Some examples of substituted alkyls include, but are not limited to, carboxyalkyl (eg, HOOC-alkyl, alkoxycarbonylalkyl and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, hydroxy Alkyl, aralkyl, (alkoxyaryl) alkyl, (sulfonylamino) alkyl (e.g. (alkylsulfonylamino) alkyl), aminoalkyl, amidoalkyl, (alicyclic) alkyl, cyanoalkyl, or haloalkyl Include.

As used herein, an "alkenyl" group refers to an aliphatic carbon group having from 2 to 8 carbon atoms (eg, 2-6 or 2-4) and containing at least one double bond. Like alkyl groups, alkenyl groups can be straight chained or branched. Examples of alkenyl groups include, but are not limited to, allyl, isoprenyl, 2-butenyl and 2-hexenyl. Alkenyl groups include one or more substituents, for example halo, cycloaliphatic, heteroalicyclic, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g. (alicyclic) carbonyl or (heterocyclic) ) Carbonyl], nitro, cyano, acyl [e.g. aliphatic carbonyl, cycloaliphatic carbonyl, arylcarbonyl, heteroalicyclic carbonyl or heteroarylcarbonyl], amido [e.g. (cycloalkylalkyl) carbon Nylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkylaminocarbonyl , Cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [eg aliphatic amino or aliphaticsulfonylamino], sulfonyl [eg alkylsulfonyl, alicyclic Sulfonyl or aryl Ponyyl], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphatic oxy, heteroalicyclic oxy, aryloxy, heteroaryloxy, aralkyloxy, Heteroarylalkoxy, alkoxycarbonyl, Optionally substituted with alkylcarbonyloxy, or hydroxy.

As used herein, an "alkynyl" group refers to an aliphatic carbon group having from 2 to 8 carbon atoms (eg, 2-6 or 2-4) and containing one or more triple bonds. Alkynyl groups can be straight chained or branched. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl. Alkynyl groups include one or more substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, Hydroxy, sulfo, mercapto, sulfanyl [e.g. aliphatic sulfanyl or cycloaliphatic sulfanyl], sulfinyl [e.g. aliphatic sulfinyl or alicyclic sulfinyl], sulfonyl [e.g. aliphatic sulfonyl, aliphatic aminosulfur Ponyl, or cycloaliphatic sulfonyl], amido [e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl , Arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (cycloalkylalkyl) carbonylamino, heteroaralkylcarbonylamino, heteroarylcarbonylamino or heteroa Aminocarbonyl], urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic, heteroalicyclic, aryl, heteroaryl, acyl [e.g. (alicyclic) carbonyl or ( Alicyclic) carbonyl], amino [eg, aliphatic amino], sulfoxy, oxo, carboxy, carbamoyl, (alicyclic) oxy, (heterocyclic) oxy, or (heteroaryl) alkoxy. .

As used herein, "amido" includes both "aminocarbonyl" and "carbonylamino". These terms are N (R ^X R ^Y ) -C (O)-or R ^Y C (O) when used alone or in combination with another group, when used in an amido group, for example at the terminal. -N (R ^X )-, when used internally, is -C (O) -N (R ^X )-or -N (R ^X ) -C (O)-(where R ^X and R ^Y are As defined). Examples of amido groups include alkylamido (e.g. alkylcarbonylamino or alkylcarbonylamino), (heterocyclic) amido, (heteroaralkyl) amido, (heteroaryl) amido, (heterocycloalkyl) ) Alkylamido, arylamido, aralkylamido, (cycloalkyl) alkylamido, or cycloalkylamido.

As used herein, an "amino" group is -NR ^X R ^Y wherein R ^X and R ^Y are independently hydrogen, alkyl, cycloaliphatic, (alicyclic) aliphatic, aryl, aliphatic, heteroalicyclic, (Heteroaliphatic) aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic) carbonyl, (alicyclic) carbonyl, ((alicyclic) aliphatic) carbonyl, arylcarbonyl, (aromatic Aliphatic) carbonyl, (heteroaliphatic) carbonyl, ((heteroaliphatic) aliphatic) carbonyl, (heteroaryl) carbonyl, or (heteroaromatic) carbonyl, each of which is defined herein and optionally substituted Say. Examples of amino groups include alkylamino, dialkylamino or arylamino. If the term "amino" is not a terminal group, it is represented by -NR ^X- (R ^X is as defined above).

As used herein, an "aryl" group, used alone or as part of a larger moiety in "aralkyl", "aralkoxy" or "aryloxyalkyl" is a monocyclic (eg phenyl), bicyclic ( Examples: indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl) and tricyclic (e.g. fluorenyl, tetrahydrofluorenyl or tetrahydroanthracenyl, anthracenyl) ring systems, where monocyclic The ring system is aromatic or at least one ring of a bicyclic or tricyclic ring system is aromatic). Bicyclic and tricyclic ring systems include benzo fused 2-3 membered carbocyclic rings. For example, a benzo fused group includes phenyl fused with two or more C _4-8 carbocyclic moieties. Aryl is aliphatic [eg, alkyl, alkenyl or alkynyl]; Alicyclic; (Alicyclic) aliphatic; Heteroalicyclic; (Heterocyclic) aliphatic; Aryl; Heteroaryl; Alkoxy; (Alicyclic) oxy; (Heterocyclic) oxy; Aryloxy; Heteroaryloxy; (Aromatic aliphatic) oxy; (Heteroaromatic aliphatic) oxy; Aroyl; Heteroaroyl; Amino; Oxo (non-aromatic carbocyclic ring of benzo fused bicyclic or tricyclic aryl); Nitro; Carboxy; Amido; Acyl [eg, aliphatic carbonyl; (Alicyclic) carbonyl; ((Alicyclic) aliphatic) carbonyl; (Aromatic aliphatic) carbonyl; (Heterocyclic) carbonyl; ((Heteroaliphatic) aliphatic) carbonyl; Or (heteroaromatic) carbonyl]; Sulfonyl [eg, aliphatic sulfonyl or aminosulfonyl]; Sulfinyl [eg, aliphatic sulfinyl or cycloaliphatic sulfinyl]; Sulfanyl [eg, aliphatic sulfanyl]; Cyano; Halo; Hydroxy; Mercapto; Sulfoxy; Urea; Thiourea; Sulfamoyl; Sulfamides; Or one or more substituents including carbamoyl. Alternatively, aryl may be unsubstituted.

Non-limiting examples of substituted aryls include haloaryl [eg mono-, di (eg p, m- dihaloaryl) and (trihalo) aryl]; (Carboxy) aryl [eg, (alkoxycarbonyl) aryl, ((aralkyl) carbonyloxy) aryl and (alkoxycarbonyl) aryl); (Amido) aryl [e.g. (Aminocarbonyl) aryl, (((alkylamino) alkyl) aminocarbonyl) aryl, (alkylcarbonyl) aminoaryl, (arylaminocarbonyl) aryl and (((heteroaryl ) Amino) carbonyl) aryl]; Aminoaryl [eg, ((alkylsulfonyl) amino) aryl or ((dialkyl) amino) aryl]; (Cyanoalkyl) aryl; (Alkoxy) aryl; (Sulfamoyl) aryl [eg, (aminosulfonyl) aryl]; (Alkylsulfonyl) aryl; (Cyano) aryl; (Hydroxyalkyl) aryl; ((Alkoxy) alkyl) aryl; (Hydroxy) aryl, ((carboxy) alkyl) aryl; (((Dialkyl) amino) alkyl) aryl; (Nitroalkyl) aryl; (((Alkylsulfonyl) amino) alkyl) aryl; ((Heterocyclic) carbonyl) aryl; ((Alkylsulfonyl) alkyl) aryl; (Cyanoalkyl) aryl; (Hydroxyalkyl) aryl; (Alkylcarbonyl) aryl; Alkylaryl; (Trihaloalkyl) aryl; p -amino- m- alkoxycarbonylaryl; p -amino- m -cyanoaryl; p- halo- m -aminoaryl; Or it comprises a (m - (alkyl) (clothing possession hwanjok) - - o) aryl.

As used herein, “aromatic aliphatic”, eg, “aralkyl” group refers to an aliphatic (eg, C _1-4 alkyl group) substituted with an aryl group. "Aliphatic "," alkyl ", and "aryl" are defined herein. An example of an aromatic aliphatic, such as an aralkyl group, is benzyl.

As used herein, "aralkyl" group is an alkyl group substituted with an aryl group: A (for example, C _{1 -4} alkyl group). Both "alkyl" and "aryl" have been defined above. An example of an aralkyl group is benzyl. Aralkyl is one or more substituents, for example aliphatic [eg carboxyalkyl, hydroxyalkyl or haloalkyl, for example alkyl, alkenyl, or alkynyl including trifluoromethyl], alicyclic [eg : Cycloalkyl or cycloalkenyl], (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, ar Alkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g. aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cyclo Alkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonyl Mino, or heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl do.

As used herein, a “bicyclic ring system” is an 8-12 membered (eg, 9, 10, or 11) structure that forms two rings, where the two rings have one or more atoms in common (eg, common Bicyclic ring systems include bicyclic (eg, bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatic, bicyclic aryl and bicyclic heteroaryl.

As used herein, an "alicyclic" group includes a "cycloalkyl" group and a "cycloalkenyl" group, each of which is optionally substituted as described below.

As used herein, a "cycloalkyl" group refers to a saturated carbocyclic monocyclic or bicyclic (fused or bridged) ring having 3 to 10 carbon atoms (eg 5 to 10). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, kubil, octahydro-indenyl, decahydro-naphthyl, bicyclo [3.2.1] Octyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] nonyl, bicyclo [3.3.2.] Decyl, bicyclo [2.2.2] octyl, adamantyl, azacycloalkyl or ((amino Carbonyl) cycloalkyl) cycloalkyl. As used herein, a "cycloalkenyl" group refers to a non-aromatic carbocyclic ring having 3 to 10 carbon atoms (eg, 4 to 8) having one or more double bonds. Examples of cycloalkenyl groups are cyclopentenyl, 1,4-cyclohexadienyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo [2.2.2] octenyl or bicyclo [3.3.1] nonenyl. The cycloalkyl or cycloalkenyl group may be one or more substituents, for example aliphatic [eg alkyl, alkenyl or alkynyl], alicyclic, (alicyclic) aliphatic, heteroalicyclic, (heteroaliphatic) aliphatic, aryl , Heteroaryl, alkoxy, (alicyclic) oxy, (heteroaliphatic) oxy, aryloxy, heteroaryloxy, (aromaticaliphatic) oxy, (heteroaromatic) oxy, aroyl, heteroaroyl, amino, amido Examples: (aliphatic) carbonylamino, (alicyclic) carbonylamino, ((alicyclic) aliphatic) carbonylamino, (aryl) carbonylamino, (aromaticaliphatic) carbonylamino, (heteroaliphatic) carbon Nylamino, ((heteroaliphatic) aliphatic) carbonylamino, (heteroaryl) carbonylamino or (heteroaromatic) carbonylamino], nitro, carboxy [e.g. HOOC-, alkoxycarbonyl or alkylcarbonyloxy ], Acyl [e.g. (alicyclic) carbonyl, (alicyclic) aliphatic) carbonyl, (aromaticaliphatic) carbonyl, Family) carbonyl, ((heteroaliphatic) aliphatic) carbonyl or (heteroaromatic) carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl [e.g. alkylsulfonyl and arylsulfonyl], Optionally substituted with sulfinyl [eg alkylsulfinyl], sulfanyl [eg alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo or carbamoyl.

As used herein, "cyclic moiety" includes cycloaliphatic, heteroalicyclic, aryl or heteroaryl, each of which is as defined above.

As used herein, the term “heteroalicyclic” includes heterocycloalkyl groups and heterocycloalkenyl groups, each of which is optionally substituted as described below.

As used herein, a "heterocycloalkyl" group is a 3 to 10 membered monocyclic or bicyclic (fused or bridged) (eg, 5 to 10 membered monocyclic or bicyclic) saturated ring structure, wherein one The above ring atoms refer to heteroatoms (eg, N, O, S or a combination thereof). Examples of heterocycloalkyl groups include piperidyl, piperazil, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-ditianyl, 1,3-dioxolanyl, oxazolidyl, Isooxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyridinyl, decahydroquinolinyl, octahydrobenzo [ b ] Thiophenethyl, 2-oxa-bicyclo [2.2.2] octyl, 1-aza-bicyclo [2.2.2] octyl, 3-aza-bicyclo [3.2.1] octyl and 2,6-dioxa -Tricyclo [3.3.1.0 ^3,7 ] nonyl. Monocyclic heterocycloalkyl groups may be fused to phenyl moieties such as tetrahydroisoquinoline. A "heterocycloalkenyl" group, as used herein, refers to a monocyclic or bicyclic (eg, 5 to 10 membered monocyclic or bicyclic) non-aromatic ring structure having one or more double bonds, one of the ring atoms These are heteroatoms (eg N, O or S). Monocyclic and bicycloheteroaliphatics are numbered according to standard chemical nomenclature.

Heterocycloalkyl or heterocycloalkenyl groups may include one or more substituents, for example aliphatic [eg, alkyl, alkenyl or alkynyl], alicyclic, (alicyclic) aliphatic, heteroalicyclic, (heteroaliphatic) aliphatic , Aryl, heteroaryl, alkoxy, (alicyclic) oxy, (heteroaliphatic) oxy, aryloxy, heteroaryloxy, (aromaticaliphatic) oxy, (heteroaromatic) oxy, aroyl, heteroaroyl, amino, Amido [e.g. (aliphatic) carbonylamino, (alicyclic) carbonylamino, ((alicyclic) aliphatic) carbonylamino, (aryl) carbonylamino, (aromaticaliphatic) carbonylamino, (heteroaliphatic) ) Carbonylamino, ((heteroaliphatic) aliphatic) carbonylamino, (heteroaryl) carbonylamino or (heteroaromatic) carbonylamino], nitro, carboxy [e.g. HOOC-, alkoxycarbonyl or alkylcarbon Nyloxy], acyl [e.g. (alicyclic) carbonyl, (alicyclic) aliphatic) carbonyl, (aromaticaliphatic) car Neyl, (heterocyclic) carbonyl, ((heteroaliphatic) aliphatic) carbonyl or (heteroaromatic) carbonyl], nitro, cyano, halo, hydroxy, mercapto, sulfonyl [e.g. alkylsulfur Optionally substituted with fonyl or arylsulfonyl], sulfinyl [e.g. alkylsulfinyl], sulfanyl [e.g. alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo or carbamoyl have.

As used herein, a "heteroaryl" group is a monocyclic, bicyclic or tricyclic ring system having 4 to 15 ring atoms, wherein one or more ring atoms are heteroatoms (e.g., N, O, S or their In combination, and the monocyclic ring system is aromatic or at least one ring of the bicyclic or tricyclic ring system is aromatic. Heteroaryl groups include benzo fused ring systems having two or three rings. For example, a benzo fused group may be a 4-8 membered heteroalicyclic moiety (e.g., indolizyl, indolyl, isoindoleyl, 3H-indolyl, indolinyl, benzo [ b ] furyl, benzo [ b ] thiophenyl , Quinolinyl or isoquinolinyl) or benzo fused with one or two. Some examples of heteroaryls are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthia Zolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo [1,3] dioxol, benzo [b] furyl, benzo [b] thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl , Furyl, cinnoyl, quinolyl, quinazolyl, cinnoyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-1,2,5-thiadiazolyl or 1,8 -Naphthyridil.

Monocyclic heteroaryls include, but are not limited to, furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, tazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4- Thiadiazolyl, 2H-pyranyl, 4-H-pyranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard subordinate nomenclature.

Bicyclic heteroaryls include, but are not limited to, indolizyl, indolyl, isoindoleyl, 3H-indolyl, indolinyl, benzo [ b ] furyl, benzo [ b ] thiophenyl, quinolinyl, isoquinolinyl, indole Lysyl, Isoindoleyl, Indolyl, Benzo [ b ] furyl, Bexo [ b ] thiophenyl, indazolyl, benzimidazil, benzthiazolyl, furinyl, 4H-quinolizyl, quinolyl, isoquinolyl, shin Nolsyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature.

Heteroaryl can be selected from one or more substituents, for example aliphatic [eg, alkyl, alkenyl or alkynyl]; Alicyclic; (Alicyclic) aliphatic; Heteroalicyclic; (Heterocyclic) aliphatic; Aryl; Heteroaryl; Alkoxy; (Alicyclic) oxy; (Heterocyclic) oxy; Aryloxy; Heteroaryloxy; (Aromatic aliphatic) oxy; (Heteroaromatic aliphatic) oxy; Aroyl; Heteroaroyl; Amino; Oxo (non-aromatic carbocyclic or heterocyclic ring of bicyclic or tricyclic heteroaryl); Carboxy; Amido; Acyl [eg, aliphatic carbonyl; (Alicyclic) carbonyl; ((Alicyclic) aliphatic) carbonyl; (Aromatic aliphatic) carbonyl; (Heterocyclic) carbonyl; ((Heteroaliphatic) aliphatic) carbonyl; Or (heteroaromatic) carbonyl]; Sulfonyl [eg, aliphatic sulfonyl or aminosulfonyl]; Sulfinyl [eg, aliphatic sulfinyl]; Sulfanyl [e.g., aliphatic sulfanyl]; Nitro; Cyano; Halo; Hydroxy; Mercapto; Sulfoxy; Urea; Thiourea; Sulfamoyl; Sulfamides; Or optionally substituted with carbamoyl. Alternatively, heteroaryl may be unsubstituted.

Non-limiting examples of substituted heteroaryls include (halo) heteroaryl [eg, mono- and di- (halo) heteroaryl]; (Carboxy) heteroaryl, such as (alkoxycarbonyl) heteroaryl; Cyanoheteroaryl; Aminoheteroaryl such as ((alkylsulfonyl) amino) heteroaryl and ((dialkyl) amino) heteroaryl]; (Amido) heteroaryl [e.g., aminocarbonylheteroaryl, ((alkylcarbonyl) amino) heteroaryl, ((((alkyl) amino) alkyl) aminocarbonyl) heteroaryl, (((heteroaryl) amino ) Carbonyl) heteroaryl, ((heterocyclic) carbonyl) heteroaryl, and ((alkylcarbonyl) amino) heteroaryl]; (Cyanoalkyl) heteroaryl; (Alkoxy) heteroaryl; (Sulfamoyl) heteroaryl such as (aminosulfonyl) heteroaryl]; (Sulfonyl) heteroaryl such as (alkylsulfonyl) heteroaryl]; (Hydroxyalkyl) heteroaryl; (Alkoxyalkyl) heteroaryl; (Hydroxy) heteroaryl; ((Carboxy) alkyl) heteroaryl; [((Dialkyl) amino) alkyl] heteroaryl; (Heterocyclic) heteroaryl; (Alicyclic) heteroaryl; (Nitroalkyl) heteroaryl; (((Alkylsulfonyl) amino) alkyl) heteroaryl; ((Alkylsulfonyl) alkyl) heteroaryl; (Cyanoalkyl) heteroaryl; (Acyl) heteroaryl [eg, (alkylcarbonyl) heteroaryl]; (Alkyl) heteroaryl, and (haloalkyl) heteroaryl [eg, trihaloalkylheteroaryl].

"Hetero aromatic aliphatic" as used herein (e.g., heteroaralkyl group) is an aliphatic substituted with a heteroaryl group: A (for example, C _{1 -4} alkyl group). "Alkali", "alkyl" and "heteroaryl" have been defined above.

"Heteroaralkyl" group, a, an alkyl group substituted with a heteroaryl group, as used herein: refers to (for example, C _{1 -4} alkyl group). Both "alkyl" and "heteroaryl" have been defined above. Heteroaralkyl includes one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, Heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, Nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (hetero Cycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, Optionally substituted with acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo or carbamoyl.

As used herein, “cyclic moieties” include cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl, each of which has been defined above.

As used herein, an "acyl" group is a formyl group or R ^X -C (O)-(e.g., -alkyl-C (O)-, also referred to as "alkylcarbonyl"), wherein R ^X and "Alkyl" is as defined above). Acetyl and pivaloyl are examples of acyl groups.

As used herein, "aroyl" or "heteroaroyl" refers to aryl-C (O)-or heteroaryl-C (O)-. The aryl and heteroaryl portions of aroyl or heteroaroyl are optionally substituted as defined above.

As used herein, "alkoxy" group refers to an alkyl-O- group, where "alkyl" is as defined above.

As used herein, a "carbamoyl" group is a structure of the formula -O-CO-NR ^x R ^y or -NR ^x -CO-OR ^z where R ^x and R ^Y are as defined above and R ^Z Refers to a group having an aliphatic, aryl, aliphatic, heteroaliphatic, heteroaryl or heteroaromatic).

As used herein, a "carboxy" group refers to -COOH, -COOR ^X , -OC (O) H, -OC (O) R ^X when used as an end group, or when used as an internal group. , -OC (O)-or -C (O) O-.

As used herein, "haloaliphatic" group refers to an aliphatic group substituted with 1, 2 or 3 halogens. For example, the term haloalkyl includes a -CF ₃ group.

As used herein, a "mercapto" group refers to -SH.

As used herein, "sulfo" group refers to -SO ₃ H or -SO ₃ R ^X when used at the end, -S (O) ₃ -when used inside.

As used herein, a "sulphamide" group, when used at its terminus, employs a structure of the formula -NR ^X -S (O) ₂ -NR ^Y R ^Z when used internally, and a formula -NR ^X -S (O ) ₂ -NR ^Y- (wherein R ^X , R ^Y and R ^Z are as defined above).

As used herein, the "sulfamoyl" group, when used at its end, uses a structure of the formula -S (O) ₂ -NR ^x R ^y or -NR ^x -S (O) ₂ -R ^z internally. When used, refers to the structure of formula -S (O) ₂ -NR ^x -or -NR ^x -S (O) _2- , wherein R ^x , R ^y and R ^Z are as defined above.

As used herein, a "sulfanyl" group refers to -SR ^X when used at the end, where R ^X is as defined above, and -S- when used internally. Examples of sulfanyl include alkylsulfanyl.

As used herein, a "sulfinyl" group refers to -S (O) -R ^X when used at the terminal, where R ^X is as defined above, and -S (O)-when used internally. Say.

As used herein , a "sulfonyl" group refers to -S (O) ₂ -R ^X when used at the terminal, where R ^X is as defined above, and -S (O) when used internally. ₂ -speaks.

As used herein, a "sulfoxy" group is -O-SO-R ^X or -SO-OR ^X when used at the terminal (where R ^X is as defined above), when used internally- OS (O)-or -S (O) -O-.

As used herein, "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine.

As used herein, the term "alkoxycarbonyl" encompassed by the term carboxy refers to a group such as alkyl-O-C (O)-, used alone or in connection with another group.

As used herein, "alkoxyalkyl" refers to an alkyl group, such as alkyl-O-alkyl-, wherein alkyl is as defined above.

As used herein, "carbonyl" refers to -C (O)-.

As used herein, "oxo" refers to = 0.

As used herein, "aminoalkyl" refers to the structure of formula (R ^X R ^Y ) N-alkyl-.

As used herein, "cyanoalkyl" refers to (NC) -alkyl-.

As used herein, a "urea" group refers to a structure of the formula -NR ^X -CO-NR ^Y R ^Z and a "thiourea" group when used at the end is a formula -NR ^X -CS-NR ^Y R ^Z When used internally refers to a group of the formula -NR ^X -CO-NR ^Y -or -NR ^X -CS-NR ^Y -wherein R ^X , R ^Y and R ^Z are as defined above .

As used herein, a "guanidino" group is a structure of the formula -N = C (N (R ^X R ^Y )) N (R ^X R ^Y ), wherein R ^X and R ^Y are as defined above. Say).

As used herein, the term "amidino" group refers to the structure of formula -C = (NR ^X ) N (R ^X R ^Y ), wherein R ^X and R ^Y are as defined above.

In general, the term "vicinal" refers to a batch of substituents on a group of 2 or more carbon atoms, wherein the substituents are bonded to adjacent carbon atoms.

In general, the term “geminal” refers to a batch of substituents on a group of 2 or more carbon atoms, wherein the substituents are bonded to the same carbon atom.

The terms "end" and "inside" refer to the position of a group within a substituent. If the group is at the end of a substituent that is not further bound to the rest of the chemical structure, the group is at the end. Carboxyalkyl, ie R ^X O (O) C-alkyl, is an example of a carboxy group used at the end. If the group is in the middle of the substituent for the end of the substituent bonded to the rest of the chemical structure, the group is internal. Alkylcarboxy (eg alkyl-C (O) O- or alkyl-OC (O)-) and alkylcarboxyaryl (eg alkyl-C (O) O-aryl- or alkyl-O (CO) -aryl-) This is an example of a carboxy group used inside.

As used herein, the term "amidino" group refers to the structure of formula -C = (NR ^X ) N (R ^X R ^Y ), wherein R ^X and R ^Y are as defined above.

As used herein, “cyclic group” includes monocyclic, bicyclic and tricyclic ring systems including alicyclic, heteroalicyclic, aryl or heteroaryl, respectively as defined above.

As used herein, “bridged bicyclic ring system” refers to a bicyclic heteroalicyclic ring system or a bicyclic alicyclic ring system, in which the ring is bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] Nonyl, bicyclo [3.2.3] nonyl, 2-oxa-bicyclo [2.2.2] octyl, 1-aza-bicyclo [2.2.2] octyl, 3-aza-bicyclo [3.2.1] octyl and 2,6-dioxa-tricyclo [3.3.1.03,7] nonyl. Bridged bicyclic ring systems include one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl and haloalkyl, such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cyclo Alkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, Heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonyl Amino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, Optionally substituted with hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo or carbamoyl.

As used herein, "aliphatic chain" refers to a branched or linear aliphatic group (eg, an alkyl group, an alkenyl group or an alkynyl group). The linear aliphatic chain has the structure of formula-[CH ₂ ] _v- , where v is 1 to 6. Branched aliphatic chains are linear aliphatic chains substituted with one or more aliphatic groups. A branched aliphatic chain has the structure of formula-[CHQ] _v- , wherein Q is hydrogen or aliphatic, but Q is aliphatic in one or more examples. The term aliphatic chain includes alkyl chains, alkenyl chains and alkynyl chains where alkyl, alkenyl and alkynyl are as defined above.

The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, as generally described above or as exemplified by the specific class, subtype and species of the present invention. As described herein, R ₁ , R ₂ , R ₃ and R ₄ in Formula I and other variables contained therein include certain groups such as alkyl and aryl. Unless otherwise noted, each of the particular groups for the variables R ₁ , R ₂ , R _3, and R ₄ and other variables contained therein may be optionally substituted with one or more substituents described herein. Each substituent of a particular group is further optionally substituted with one to three of halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl and alkyl. For example, the alkyl group may be substituted with alkylsulfanyl, which may be optionally substituted with one to three of halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl and alkyl. have. As a further example, the cycloalkyl moiety of (cycloalkyl) carbonylamino may be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl and alkyl. When two alkoxy groups are bonded to the same atom or adjacent atoms, the two alkoxy groups may form a ring together with the atom (s) to which they are attached.

In general, the term "substituted" refers to the replacement of hydrogen radicals in a given structure with radicals of the specified substituents, whether or not preceded by the term "optionally". Specific substituents are described in the definitions above and in the descriptions of the compounds and examples thereof below. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and in any given structure, if one or more positions can be substituted with one or more substituents selected from the specified group, the substituents are all It may be the same or different in position. Ring substituents, such as heterocycloalkyl, may be bonded to another ring, such as cycloalkyl, for example to form a spiro-bicyclic ring system, in which both rings share one common atom. Those skilled in the art will recognize that combinations of substituents envisioned by the present invention are combinations that form stable or chemically viable compounds.

As used herein, the term “up to” refers to an integer equal to or less than zero or a number following the term. For example, "3 or less" means any of 0, 1, 2, and 3.

As used herein, the term “stable or chemically viable” is substantially used when subjected to conditions that allow the preparation, detection, and preferably recovery, purification, and use of one or more of the purposes described herein, for the preparation of the compound. Refers to a compound that does not change. In some embodiments, a stable compound or chemically viable compound is one that is substantially unchanged when maintained at temperatures below 40 ° C. for one week or longer in the absence of moisture or other chemically reactive conditions.

As used herein, an effective amount is defined as the amount required to confer a therapeutic effect on a treated patient and is typically measured based on the age, surface area, weight and condition of the patient. Dose correlations (based on milligrams per square meter of body surface) for animals and humans are described in Freireich et al., Cancer Chemother. Rep. , 50: 219 (1966). Body surface area can be approximately estimated from the height and weight of the patient. See, eg, Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" refers to a mammal, including a human.

Unless stated otherwise, the structures described herein include all isomeric forms of the structure (e.g., enantiomers, diastereomers and geometric (or conformational)), for example the R and S forms for each asymmetric center, It is meant to include (Z) and (E) double bond isomers, and (Z) and (E) form isomers. Therefore, enantiomeric, diastereomeric and geometric (or conformational) mixtures of the compounds of the invention as well as the single stereochemical isomers are within the scope of the invention. Unless stated otherwise, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless stated otherwise, the structures described herein are also meant to include different compounds only in the presence of one or more isotope rich elements. For example, compounds having a structure of the present invention except for replacement of hydrogen with deuterium or tritium or replacement of carbon with ¹³ C- or ¹⁴ C-rich carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical instruments or probes in biological assays.

compound

Compounds of the invention are useful modulators of ABC transporters and are useful for the treatment of ABC transport mediated diseases.

A. General Compound

The present invention includes a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Formula I

In the above formula (I)

Each R ₁ is optionally substituted C _{1 -6} aliphatic, optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted C _{3 -10} cycloaliphatic, an optionally substituted 3-to 10 restore possession hwanjok, carboxy [e.g. Hydroxycarbonyl or alkoxycarbonyl], amido [eg aminocarbonyl], amino, halo, or hydroxy, provided that at least one R ₁ is optionally substituted at the 5 or 6 position of the pyridyl ring Alicyclic, optionally substituted heteroalicyclic, optionally substituted aryl or optionally substituted heteroaryl,

R ₂ are each a hydrogen, an optionally substituted C _{1 -6} aliphatic, an optionally substituted C _{3 -6} aliphatic, optionally substituted phenyl or optionally substituted heteroaryl,

R ₃ and R _'3 are each together with the carbon atom to which they are attached, forms an optionally substituted C _{3 -7} cycloaliphatic or an optionally substituted repeat possession hwanjok,

Each R ₄ is optionally substituted aryl or optionally substituted heteroaryl,

n is 1, 2, 3 or 4, respectively.

In another aspect, the present invention includes a compound of formula la or a pharmaceutically acceptable salt thereof.

In the above formula (Ia)

One of G ₁ and G ₂ is nitrogen, the other is carbon,

R ₁ , R ₂ , R ₃ , R ' ₃ , R ₄ and n are as defined above.

Certain aspects

A. Substituent R ₁

R ₁ each independently represent an optionally substituted C _{1 -6} aliphatic, optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted C _{3 -10} won cycloaliphatic, an optionally substituted 3-to 10 restore possession hwanjok, carboxy Eg hydroxycarbonyl or alkoxycarbonyl, amido [eg aminocarbonyl] amino, halo, or hydroxy.

In some embodiments, one of R ₁ is optionally substituted C _{1 -6} aliphatic. In some examples, one of R ₁ is optionally substituted C _{1 -6} alkyl, optionally substituted C _{2 -6} alkenyl, or an optionally substituted C _{2 -6-alkynyl.} In some examples, one of R ₁ is C _{1 -6} alkyl, C _{2 -6} alkenyl or C _2-6 alkynyl.

In some embodiments, one R ₁ is aryl or heteroaryl having 1, 2 or 3 substituents. In some instances, one R ₁ is monocyclic aryl or heteroaryl. In some embodiments, R ₁ is aryl or heteroaryl having 1, 2 or 3 substituents. In some instances, R ₁ is monocyclic aryl or heteroaryl.

In some embodiments, one or more R ₁ is optionally substituted aryl or optionally substituted heteroaryl, and R ₁ is bonded to the core structure at the 6 position of the pyridine ring.

In some embodiments, one or more R ₁ is optionally substituted aryl or optionally substituted heteroaryl, and R ₁ is bonded to the core structure at the 5-position of the pyridine ring.

In some embodiments, one R ₁ is phenyl having up to 3 substituents. In some embodiments, R ₁ is phenyl having up to 3 substituents.

In some embodiments, one R ₁ is a heteroaryl ring having up to 3 substituents. In certain embodiments, one R ₁ is a monocyclic heteroaryl ring having up to 3 substituents. In other embodiments, one R ₁ is a bicyclic heteroaryl ring having up to 3 substituents. In some embodiments, R ₁ is a heteroaryl ring having up to 3 substituents. In certain embodiments, R ₁ is a monocyclic heteroaryl ring having up to 3 substituents. In other embodiments, R ₁ is a bicyclic heteroaryl ring having up to 3 substituents.

In some embodiments, one R ₁ is carboxy [eg, hydroxycarbonyl or alkoxycarbonyl]. Or one R ₁ is amido [eg, aminocarbonyl]. Or one R ₁ is amino. Or halo. Or cyano. Or hydroxyl.

In some embodiments, R ₁ is hydrogen, methyl, ethyl, i-propyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, F, Cl, methoxy, ethoxy, i-propoxy, t-butoxy, CF ₃ , OCF ₃ , CN, hydroxyl, or amino. In some instances, R ₁ is hydrogen, methyl, methoxy, F, CF ₃ or OCF ₃ . In some instances, R ₁ can be hydrogen. Alternatively, R ₁ may be methyl. Alternatively, R ₁ may be CF ₃ . Alternatively, R ₁ may be methoxy.

In some embodiments, R ₁ is halo, oxo, or optionally substituted aliphatic, cycloaliphatic, heteroalicyclic, amino [eg, (aliphatic) amino], amido [eg, aminocarbonyl, ((aliphatic) amino) Carbonyl, and ((aliphatic) ₂ amino) carbonyl], carboxy [e.g. Alkoxycarbonyl and hydroxycarbonyl], sulfamoyl [e.g. Aminosulfonyl, ((aliphatic) ₂ amino) sulfonyl, (( Alicyclic) aliphatic) aminosulfonyl, and ((alicyclic) amino) sulfonyl], cyano, alkoxy, aryl, heteroaryl [e.g. monocyclic heteroaryl and bicycloheteroaryl], sulfonyl [e.g. aliphatic Sulfonyl or (heteroalicyclic) sulfonyl], sulfinyl [e.g. aliphatic sulfinyl], aroyl, heteroaroyl, or heteroalicyclic carbonyl.

In some embodiments, R ₁ is substituted with halo. Examples of R ₁ substituents include F, Cl and Br. In some instances, R ₁ is substituted with F.

In some embodiments, R ₁ is substituted with an optionally substituted aliphatic. Examples of R ₁ substituents are optionally substituted alkoxyaliphatic, heteroalicyclic, aminoalkyl, hydroxyalkyl, (heterocycloalkyl) aliphatic, alkylsulfonylaliphatic, alkylsulfonylaminoaliphatic, alkylcarbonylaminoaliphatic, alkylaminoaliphatic Or alkylcarbonylaliphatic.

In some embodiments, R ₁ is substituted with an optionally substituted amino. Examples of R ₁ substituents include aliphatic carbonylamino, aliphatic amino, arylamino, or aliphaticsulfonylamino.

In some embodiments, R ₁ is substituted with sulfonyl. Examples of R ₁ substituents are heteroalicyclic sulfonyl, aliphatic sulfonyl, aliphatic aminosulfonyl, aminosulfonyl, aliphatic carbonylaminosulfonyl, alkoxyalkylheterocycloalkylsulfonyl, alkylheterocycloalkylsulfonyl, alkylaminosul Phonyl, cycloalkylaminosulfonyl, (heterocycloalkyl) alkylaminosulfonyl, and heterocycloalkylsulfonyl.

In some embodiments, R ₁ is substituted with carboxy. Examples of R ₁ substituents include alkoxycarbonyl and hydroxycarbonyl.

In some embodiments, R ₁ is substituted with an amido. Examples of R ₁ substituents include alkylaminocarbonyl, aminocarbonyl, ((aliphatic) ₂ amino) carbonyl and [((aliphatic) aminoaliphatic) amino] carbonyl.

In some embodiments, R ₁ is substituted with carbonyl. Examples of R ₁ substituents include arylcarbonyl, alicyclic carbonyl, heteroalicyclic carbonyl, and heteroarylcarbonyl.

In some embodiments, R ₁ is hydrogen. In some embodiments, R ₁ is —Z ^A R ₅ wherein Z ^A is each independently a branched or linear C _1-6 aliphatic chain which is bonded or optionally substituted, wherein up to two carbon units of Z ^A are optionally Independently -CO-, -CS-, -CONR ^A- , -CONR ^A NR ^A- , -CO _2- , -OCO-, -NR ^A CO _2- , -O-, -NR ^A CONR ^A -,- OCONR ^A- , -NR ^A NR ^A- , -NR ^A CO-, -S-, -SO-, -SO _2- , -NR ^A- , -SO ₂ NR ^A- , -NR ^A SO _2- , or Is replaced by -NR ^A SO ₂ NR ^A- . R ₅ is each independently R ^A , halo, —OH, —NH ₂ , —NO ₂ , —CN, —CF ₃ , or —OCF ₃ . Each R ^A is independently C _1-8 aliphatic, cycloaliphatic, heteroalicyclic, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, or 3 R ^D. Each R ^D is —Z ^D R ₉ wherein Z ^D is each independently a bonded or optionally substituted branched or linear C _1-6 aliphatic chain, wherein up to two carbon units of Z ^D are optionally independently -CO-, -CS-, -CONR ^E- , -CONR ^E NR ^E- , -CO _2- , -OCO-, -NR ^E CO _2- , -O-, -NR ^E CONR ^E- , -OCONR ^E -, -NR ^E NR ^E- , -NR ^E CO-, -S-, -SO-, -SO _2- , -NR ^E- , -SO ₂ NR ^E- , -NR ^E SO _2- , or -NR ^E SO ₂ NR ^E -is substituted). R ₉ are each independently R ^E , halo, —OH, —NH ₂ , —NO ₂ , —CN, —CF ₃ , or —OCF ₃ . Each R ^E is independently hydrogen, optionally substituted C _1-8 aliphatic, optionally substituted alicyclic, optionally substituted heteroalicyclic, optionally substituted aryl, or optionally substituted heteroaryl.

In some embodiments, R ^D are each -Z ^D R ₉ [where independently, Z ^D are each independently a bond or an optionally substituted branched or linear C _{1 -6} aliphatic chain (wherein no more than 2 carbon of Z ^D Units are optionally independently -O-, -NHC (O)-, -C (O) NR ^E- , -SO _2- , -NHSO _2- , -NHC (O)-, -NR ^E SO ₂ -,- SO ₂ NH—, —SO ₂ NR ^E —, —NH—, or —C (O) O—. In some embodiments, one carbon unit of Z ^D is replaced by —O—. Or -NHC (O)-. Or substituted by -C (O) NR ^E- . Or, -SO _2- . Or, -NHSO _2- . Or by -NHC (O)-. Or replaced by -SO-. Or, -NR ^E SO _2- . Or, -SO ₂ NH-. Or, -SO ₂ NR ^E- . Or by -NH-. Or by -C (O) O-.

In some embodiments, R ₉ is hydrogen. In some embodiments, R ₉ is independently optionally substituted aliphatic. In some embodiments, R ₉ is optionally substituted alicyclic. Or optionally substituted heteroalicyclic. Or optionally substituted aryl. Or optionally substituted heteroaryl. Or halo.

In some embodiments, one R ₁ is aryl or heteroaryl, each optionally substituted with one, two or three R ^D , wherein R ^D is as defined above.

In some embodiments, one R ₁ is carboxy [eg, hydroxycarbonyl or alkoxycarbonyl]. Or one R ₁ is amido [eg, aminocarbonyl]. Or one R ₁ is amino. Or halo. Or cyano. Or hydroxyl.

In some embodiments, one R ₁ bonded to the 5 or 6 position of the pyridyl ring is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 R ^D , wherein R ^D is as defined above. In some embodiments, one R ₁ bonded to the 5 or 6 position of the pyridyl ring is phenyl optionally substituted with 1, 2 or 3 R ^D , wherein R ^D is as defined above. In some embodiments, one R ₁ bonded to the 5 or 6 position of the pyridyl ring is heteroaryl optionally substituted with 1, 2 or 3 R ^D. In some embodiments, one R ₁ bonded to the 5 or 6 position of the pyridyl ring is a 5 or 6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur to be. In other embodiments, the 5- or 6-membered heteroaryl is substituted with one R ^D.

In some embodiments, one R ₁ bonded to the 5 or 6 position of the pyridyl ring is phenyl substituted with one R ^D. In some embodiments, one R ₁ bonded to the 5 or 6 position of the pyridyl ring is phenyl substituted with two R ^D. In some embodiments, one R ₁ bonded to the 5 or 6 position of the pyridyl ring is phenyl substituted with 3 R ^D.

(Z-1) 또는

(Z-2)[여기서, W₁은 -C(O)-, -SO₂-, 또는 -CH₂-이고; D는 H, 하이드록실, 또는 지방족, 지환족, 알콕시 및 아미노로부터 선택된 임의로 치환된 그룹이며; R^D는 위에서 정의한 바와 같다]으로 나타낸다.In some embodiments, R ₁ is

(Z-1) or

(Z-2) wherein W ₁ is —C (O) —, —SO ₂ —, or —CH ₂ —; D is H, hydroxyl, or an optionally substituted group selected from aliphatic, cycloaliphatic, alkoxy and amino; R ^D is as defined above].

In some embodiments, W ₁ is —C (O) —. Or W ₁ is —SO ₂ —. Or W ₁ is —CH ₂ —.

In some embodiments, D is OH. Or, D is a C ₃ -C ₈ aliphatic group optionally substituted aliphatic or an optionally substituted C _{1 -6.} Or D is optionally substituted alkoxy. Or D is optionally substituted amino.

(여기서, A 및 B는 각각 독립적으로 H, 임의로 치환된 C_{1 -6} 지방족, 임의로 치환된 C₃-C₈ 지환족이거나; A와 B는 함께 임의로 치환된 3-7원 복소지환족 환을 형성한다)이다.In some examples, D

(Wherein, A and B are each independently H, optionally substituted C _{1 -6} aliphatic, or a C ₃ -C ₈ aliphatic group optionally substituted; A and B are optionally substituted with 3-7 restore possession with hwanjok ring To form).

In some embodiments, A is H, B is a C _{1 -6} aliphatic group optionally substituted. In some embodiments, B is substituted with 1, 2 or 3 substituents. Or A and B are both H. Exemplary substituents include optionally substituted groups selected from oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, dialkylamino, or cycloaliphatic, heteroalicyclic, aryl and heteroaryl.

In some embodiments, A is H, B is a C _{1 -6} aliphatic group optionally substituted. Or A and B are both H. Exemplary substituents include oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, and optionally substituted heteroalicyclics.

In some embodiments, B is oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, optionally substituted C _{1 -6} alkyl, or alicyclic, carrying clothing hwanjok, aryl, and an optionally substituted group selected from heteroaryl, to be. In some embodiments, B is oxo, C _{1 -6} alkyl, hydroxy, hydroxy - (C _{1 -6)} alkyl, (C _{1 -6)} alkoxy, (C _{1 -6)} alkoxycarbonyl (C _{1 -6)} alkyl, C _{3 -8} cycloaliphatic, 3-8 restore possession hwanjok is substituted with phenyl, and a 5-10 membered heteroaryl. In one example, B is a C _{1 -6} alkyl optionally substituted by a substituted phenyl.

In some embodiments, A and B together form an optionally substituted 3-7 membered heteroalicyclic ring. In some instances, the heteroalicyclic ring is optionally substituted with 1, 2 or 3 substituents. Exemplary such rings include optionally substituted pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl. Exemplary substituents for such rings include halo, oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, acyl (eg alkylcarbonyl), amino, amido and carboxy. In some embodiments, the substituent is halo, oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, amido, or carboxy.

In some embodiments, R ^D is an optionally substituted group selected from hydrogen, halo, or aliphatic, cycloaliphatic, amino, hydroxy, alkoxy, carboxy, amido, carbonyl, cyano, aryl, and heteroaryl. In some instances, R ^D is hydrogen, halo, optionally substituted C _1-6 aliphatic, or optionally substituted alkoxy. In some instances, R ^D is hydrogen, F, Cl, optionally substituted C _1-6 alkyl, or optionally substituted —O (C _1-6 alkyl). Examples of R ^D are hydrogen, F, Cl, methyl, ethyl, i -propyl, t -butyl, -OMe, -OEt, i -propoxy, t-butoxy, CF ₃ , or -OCF ₃ . In some instances, R ^D is hydrogen, F, methyl, methoxy, CF ₃ , or —OCF ₃ . R ^D may be hydrogen. R ^D may be F. R ^D may be methyl. R ^D may be methoxy.

(Z)[여기서, W₁는 -C(O)-, -SO₂-, 또는 -CH₂-이고; A 및 B 각각은 독립적으로 H, 임의로 치환된 C_{1 -6} 지방족, 임의로 치환된 C₃-C₈ 지환족이거나; A와 B는 함께 임의로 치환된 3-7원 복소지환족 환을 형성한다] 으로 나타낸다.In some embodiments, R ₁ formula

(Z) wherein W ₁ is —C (O) —, —SO ₂ —, or —CH ₂ —; A and B each independently represent H, an optionally substituted C _{1 -6} aliphatic, an optionally substituted C ₃ -C ₈ cycloaliphatic or; A and B together form an optionally substituted 3-7 membered heteroalicyclic ring].

In some embodiments, one R ₁ bonded to the 5 or 6 position of the pyridyl ring is an alicyclic or heteroalicyclic optionally substituted with 1, 2 or 3 R ^D , respectively, wherein R ^D is —Z ^D R ₉ (wherein, Z ^D are each independently a bond or an optionally branched or linear C _{1 -6} aliphatic chain-substituted, 2 or fewer carbon units of Z ^D is optionally independently -CO-, -CS-, -CONR ^E -, -CONR ^E NR ^E- , -CO _2- , -OCO-, -NR ^E CO _2- , -O-, -NR ^E CONR ^E- , -OCONR ^E- , -NR ^E NR ^E- , -NR ^E CO-, -S-, -SO-, -SO _2- , -NR ^E- , -SO ₂ NR ^E- , -NR ^E SO _2- , or -NR ^E SO ₂ NR ^E -is replaced by R ₉ are independently R ^E, _{halo, -OH, -NH 2, -NO 2} , -CN, -CF 3, or -OCF _3, and, R ^E is independently hydrogen, optionally substituted C _{1 -8} aliphatic, optionally Substituted alicyclic, optionally substituted heteroalicyclic, optionally substituted aryl, or optionally substituted heteroaryl).

In some instances, one R ₁ bonded to the 5 or 6 position of the pyridyl ring is an optionally substituted C ₃ -C ₈ alicyclic group.

In some embodiments, one R ₁ bonded to the 5 or 6 position of the pyridyl ring is optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted C ₃ -C ₈ cycloalkenyl.

In some embodiments, one R ₁ bonded to the 5 or 6 position of the pyridyl ring is C ₃ -C ₈ cycloalkyl or C ₃ -C ₈ cycloalkenyl. Examples of cycloalkyl and cycloalke include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.

In some embodiments, R ₁ is of the formula:

In some instances, R ₁ is selected from the following formula:

B. Substituent R ₂

R ₂ may each be hydrogen. R ₂ may be each C _{1 -6} aliphatic, C _{3 -6} aliphatic, phenyl, and a group selected from optionally substituted heteroaryl.

In some embodiments, R ₂ is an optionally substituted C _{1 -6} aliphatic with 1, 2, or 3 halo, C _{1 -2} aliphatic or alkoxy. In some instances, R ₂ can be substituted methyl, ethyl, propyl, or butyl. In some instances, R ₂ can be methyl, ethyl, propyl, or butyl.

In some embodiments, R ₂ is hydrogen.

C. Substituent R ₃ and R ' ₃

R ₃ and R _'3 are formed each with the carbon atoms to which they are attached, C _{3 -7} alicyclic or heterocyclic possession hwanjok (each of which is optionally substituted with one, two or three substituents). In some embodiments, R ₃ and R _'3 together with the carbon atom to which they are attached, C _{3 -7} alicyclic or C _{3 -7} clothing possession hwanjok [each of which is 1, 2 or 3 -Z ^B R ₇ (wherein each of Z ^B are independently a bond or an optionally substituted branched or linear C _{1 -4} aliphatic chain, two carbon units of Z or fewer of ^B is optionally independently -CO-, -CS-, -CONR ^B -, -CONR ^B NR ^B- , -CO _2- , -OCO-, -NR ^B CO _2- , -O-, -NR ^B CONR ^B- , -OCONR ^B- , -NR ^B NR ^B- , -NR ^B CO-, -S-, -SO-, -SO _2- , -NR ^B- , -SO ₂ NR ^B- , -NR ^B SO ₂ -or -NR ^B SO ₂ NR ^B -is replaced; R ₇ They are each independently selected from R ^B, _{halo, -OH, -NH 2, -NO 2} , -CN, -CF 3, or -OCF _3, and; R ^B is independently hydrogen, optionally substituted C _{1 -8} aliphatic, Optionally substituted alicyclic, optionally substituted heteroalicyclic, optionally substituted aryl, or optionally substituted heteroaryl).

In some embodiments, R ₃ and R ′ ₃ together with the carbon atoms to which they are attached form a 3, 4, 5, or 6 membered alicyclic optionally substituted with 1, 2 or 3 substituents. In some instances, R ₃ , R ′ ₃ and the carbon atoms to which they are attached form an optionally substituted cyclopropyl group. In some alternative embodiments, R ₃ , R ′ ₃ and the carbon atoms to which they are attached form an optionally substituted cyclobutyl group. In some other embodiments, R ₃ , R ′ ₃ , and the carbon atoms to which they are attached, form an optionally substituted cyclopentyl group. In other embodiments, R ₃ , R ′ ₃ and the carbon atoms to which they are attached form an optionally substituted cyclohexyl group. In further embodiments, R ₃ , R ′ ₃ and the carbon atoms to which they are attached form unsubstituted cyclopropyl.

In some embodiments, R ₃ and R ′ ₃ together with the carbon atoms to which they are attached form an optionally substituted 5, 6, or 7 membered heteroalicyclic. In another embodiment, R ₃ and R ′ ₃ together with the carbon atoms to which they are attached form an optionally substituted tetrahydropyranyl group.

In some embodiments, to form the R ₃ and R _'3 is in possession hwanjok clothing together with the carbon atom to which they are attached, it does not is not C _{3 -7} alicyclic or substituted. In some instances, R ₃ and R ′ ₃ together with the carbon atoms to which they are attached form unsubstituted cyclopropyl, unsubstituted cyclopentyl, or unsubstituted cyclohexyl.

D. Substituent R ₄

Each R ₄ is independently optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, R ₄ is 6 to 10 membered (eg, 7 to 10 membered) aryl optionally substituted with 1, 2 or 3 substituents. Examples of R ₄ include optionally substituted benzene, naphthalene, or indene. Alternatively, examples of R ₄ may be optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted indenyl.

In some embodiments, R ₄ is optionally substituted heteroaryl. Examples of R ₄ include monocyclic and bicyclic heteroaryl, such as benzo fused ring systems, wherein phenyl is fused to one or two 4-8 membered heteroalicyclics.

In some embodiments, R ₄ is aryl or heteroaryl, optionally substituted with 1, 2 or 3 -Z ^C R ₈ , respectively. In some embodiments, R ₄ is aryl optionally substituted with 1, 2 or 3 -Z ^C R ₈ . In some embodiments, R ₄ is phenyl optionally substituted with 1, 2 or 3 -Z ^C R ₈ . Or R ₄ is heteroaryl optionally substituted with 1, 2 or 3 —Z ^C R ₈ . Z ^C is independently a branched or linear C _1-6 aliphatic chain, each independently bonded or optionally substituted, wherein up to two carbon atoms of Z ^C are optionally independently —CO—, —CS—, —CONR ^C —, -CONR ^C NR ^C- , -CO _2- , -OCO-, -NR ^C CO _2- , -O-, -NR ^C CONR ^C- , -OCONR ^C- , -NR ^C NR ^C- , -NR ^C CO -, -S-, -SO-, -SO _2- , -NR ^C- , -SO ₂ NR ^C- , -NR ^C SO _2- , or -NR ^C SO ₂ NR ^C- . R ₈ are each independently R ^C , halo, —OH, —NH ₂ , —NO ₂ , —CN, —CF ₃ , or —OCF ₃ . Each R ^C is independently hydrogen, optionally substituted C _1-8 aliphatic, optionally substituted alicyclic, optionally substituted heteroalicyclic, optionally substituted aryl, or optionally substituted heteroaryl.

In certain embodiments, two -Z ^C R ₈ are taken together with the carbon to which they are attached, independently represents a group consisting of O, NH, NR, and S ^C ring to three selected from (wherein, R ^C are as defined herein) To form a 4-8 membered saturated, partially saturated or aromatic ring having atoms.

In some embodiments, R ₄ is selected from the following formula:

E. Exemplary Compound Class

In some embodiments, R ₁ is an optionally substituted cyclic group bonded to the 5 or 6 position core structure of the pyridine ring.

In some instances, R ₁ is optionally substituted aryl bonded at the 5-position of the pyridine ring. In other instances, R ₁ is optionally substituted aryl bonded at the 6 position of the pyridine ring.

In a further example, R ₁ is optionally substituted heteroaryl bonded at the 5-position of the pyridine ring. In other embodiments, R ₁ is optionally substituted heteroaryl bonded at the 6 position of the pyridine ring.

In other embodiments, R ₁ is optionally substituted alicyclic or optionally substituted heteroalicyclic bonded to the 5 or 6 position of the pyridine ring.

Accordingly, another aspect of the present invention provides a compound of Formula II or a pharmaceutically acceptable salt thereof.

In the above formula (II)

R ₁ , R ₂ , R ₃ , R ' ₃ , and R ₄ are as defined in formula (I).

In some embodiments, R ₁ is each aryl or heteroaryl optionally substituted with 1, 2 or 3 R ^D wherein R ^D is Z ^D R ₉ {wherein Z ^D is independently a branched or linear substituted or optionally substituted Phosphorus is C _1-6 aliphatic chain and up to 2 carbon units of Z ^D are optionally independently -CO-, -CS-, -CONR ^E- , -CONR ^E NR ^E- , -CO _2- , -OCO-, -NR ^E CO _2- , -O-, -NR ^E CONR ^E- , -OCONR ^E- , -NR ^E NR ^E- , -NR ^E CO-, -S-, -SO-, -SO ₂ -,- NR ^E- , -SO ₂ NR ^E- , -NR ^E SO _2- , or -NR ^E SO ₂ NR ^E- ; Each R ₉ is independently R ^E , halo, —OH, —NH ₂ , —NO ₂ , —CN, —CF ₃ , or —OCF ₃ ; Each R ^E is independently hydrogen, an optionally substituted C _1-8 aliphatic group, an optionally substituted alicyclic, an optionally substituted heteroalicyclic, an optionally substituted aryl, or an optionally substituted heteroaryl.

In some embodiments, R ₁ is an alicyclic or heteroalicyclic, each optionally substituted with 1, 2 or 3 R ^D , wherein R ^D is as defined above.

Another aspect of the invention provides a compound of Formula III or a pharmaceutically acceptable salt thereof.

In formula (III) above,

R ₁ , R ₂ , R ₃ , R ' ₃ , and R ₄ are as defined in formula (I).

In some embodiments, R ₁ is aryl or heteroaryl, each optionally substituted with 1, 2 or 3 R ^D wherein R ^D is —Z ^D R ₉ {where each Z ^D is independently a bonded or optionally substituted branch C _1-6 aliphatic chain, linear or linear, and up to two carbon units of Z ^D are optionally independently —CO—, —CS—, —CONR ^E —, —CONR ^E NR ^E —, —CO ₂ —, OCO-, -NR ^E CO _2- , -O-, -NR ^E CONR ^E- , -OCONR ^E- , -NR ^E NR ^E- , -NR ^E CO-, -S-, -SO-, -SO ₂ -, -NR ^E- , -SO ₂ NR ^E- , -NR ^E SO _2- , or -NR ^E SO ₂ NR ^E- ; Each R ₉ is independently R ^E , halo, —OH, —NH ₂ , —NO ₂ , —CN, —CF ₃ , or —OCF ₃ ; Each R ^E is independently hydrogen, an optionally substituted C _1-8 aliphatic group, an optionally substituted alicyclic, an optionally substituted heteroalicyclic, an optionally substituted aryl, or an optionally substituted heteroaryl.

In some embodiments, R ₁ is an alicyclic or heteroalicyclic, each optionally substituted with 1, 2 or 3 R ^D , wherein R ^D is as defined above.

In another aspect, the present invention includes a compound of Formula IV or a pharmaceutically acceptable salt thereof.

In the above formula (IV)

R ₂ , R ₃ , R ' ₃ , and R ₄ are as defined in formula (I).

R ^D is -Z ^D R ₉ [wherein, Z ^D are each independently a bond or an optionally substituted branched or linear C _{1 -6} aliphatic chain, two carbon units of Z ^D is less than or optionally independently -CO- , -CS-, -CONR ^E- , -CONR ^E NR ^E- , -CO _2- , -OCO-, -NR ^E CO _2- , -O-, -NR ^E CONR ^E- , -OCONR ^E -,- NR ^E NR ^E- , -NR ^E CO-, -S-, -SO-, -SO _2- , -NR ^E- , -SO ₂ NR ^E- , -NR ^E SO _2- , or -NR ^E SO ₂ NR ^E -is substituted for.

R ₉ is independently R ^E , halo, —OH, —NH ₂ , —NO ₂ , —CN, —CF ₃ , or —OCF ₃ .

Each R ^E is independently hydrogen, optionally substituted C _1-8 aliphatic group, optionally substituted alicyclic, optionally substituted heteroalicyclic, optionally substituted aryl, or optionally substituted heteroaryl.

In some embodiments, Z ^D are independently a bond or an optionally substituted branched or linear C _{1 -6} one carbon units of an aliphatic chain, Z ^D is ^{_{-SO 2 -, -CONR E -,}} - NR E SO 2 Or is optionally substituted by -SO ₂ NR ^E- . For example, Z ^D is branched or linear C _{1 -6} aliphatic chain, optionally substituted, one carbon unit of Z ^D is -SO ₂ - is optionally replaced by. In other instances, R ₉ is optionally substituted heteroaryl or optionally substituted heteroalicyclic. In a further example, R ₉ is an optionally substituted heteroalicyclic having 1 to 2 nitrogen atoms, and R ₉ directly bonds to -SO ₂ -via ring nitrogen.

In another aspect, the invention includes a compound of formula Va or Vb or a pharmaceutically acceptable salt thereof.

In the above formulas Va and Vb,

T is an optionally substituted C _{1 -2} aliphatic chain, wherein each carbon unit is -CO-, -CS-, -COCO-, -SO _2- , -B (OH)-, or -B (O (C _1-6 alkyl)), - it is optionally replaced independently by; an,

R ₁ 'and R ₁ "are each independently a bond or an optionally substituted C _{1 -6} aliphatic, optionally substituted aryl, optionally substituted heteroaryl, 3-to 10-membered optionally substituted cycloaliphatic, an optionally substituted 3-to 10 membered heteroalicyclic, carboxy, amido, amino, halo, or hydroxy,

R ^D1 is bonded to a 3 "or 4" carbon,

R ^D1 and R ^D2 -Z is R ^D, each ₈ [Here, Z ^D are independently a bond or an optionally substituted branched or linear C _{1 -6} aliphatic chain, two carbon units ^of Z ^D is less than or optionally independently -CO-, -CS-, -CONR ^E- , -CONR ^E NR ^E- , -CO _2- , -OCO-, -NR ^E CO _2- , -O-, -NR ^E CONR ^E- , -OCONR ^E -, -NR ^E NR ^E- , -NR ^E CO-, -S-, -SO-, -SO _2- , -NR ^E- , -SO ₂ NR ^E- , -NR ^E SO _2- , or -NR ^E SO ₂ NR ^E -is substituted by

R ₉ is independently R ^E , halo, —OH, —NH ₂ , —NO ₂ , —CN, —CF ₃ , or —OCF _3, or

R ^D1 and R ^D2 together with the atoms to which they are attached form a 3-8 membered saturated, partially unsaturated or aromatic ring having up to 3 ring members independently selected from the group consisting of O, NH, NR ^E and S and,

R ^E are each independently hydrogen, optionally substituted C _{1 -8} aliphatic, optionally substituted cycloaliphatic, an optionally substituted repeat possession hwanjok, aryl, optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, T is optionally substituted -CH _2- . In some other embodiments, T is optionally substituted -CH ₂ CH _2- .

In some embodiments, T is -Z ^E R ₁₀ [wherein, Z ^E are each independently a bond or an optionally substituted branched or linear C _{1 -6} aliphatic chain, two carbon units of no more than the Z ^E is optionally independently -CO-, -CS-, -CONR ^F- , -CONR ^F NR ^F- , -CO _2- , -OCO-, -NR ^F CO _2- , -O-, -NR ^F CONR ^F- , -OCONR ^F -, -NR ^F NR ^F- , -NR ^F CO-, -S-, -SO-, -SO _2- , -NR ^F- , -SO ₂ NR ^F- , -NR ^F SO _2- , or -NR ^Is replaced by ^F SO ₂ NR ^F −; R ₁₀ is independently R ^F , halo, —OH, —NH ₂ , —NO ₂ , —CN, —CF ₃ , or —OCF ₃ ; R ^F is optionally substituted with independently hydrogen, optionally substituted C _{1 -8} aliphatic, optionally substituted cycloaliphatic, an optionally substituted repeat possession hwanjok, optionally substituted aryl, or optionally a heteroaryl substituted. In one example, Z ^E is -O-.

In some embodiments, R ₁₀ is optionally substituted C _{1 -6} alkyl, optionally substituted C _{2 -6} alkenyl, may be optionally substituted with C _{3 -7} cycloaliphatic, or an optionally substituted C _{6 -10} aryl group. In one embodiment, R ₁₀ is methyl, ethyl, i -propyl, or t -butyl.

In some embodiments, up to two carbon units of T are optionally substituted by -CO-, -CS-, -B (OH)-, or -B (O (C _1-6 alkyl)-.

, -C(페닐)₂-, -B(OH)-, 및 -CH(OEt)-로 이루어진 그룹으로부터 선택된다. 일부 양태에서는, T는 -CH₂-, -CF₂-, -C(CH₃)₂-,

또는 -C(페닐)₂-이다. 다른 양태에서는, T is -CH₂H₂-, -C(O)-, -B(OH)-, 및 -CH(OEt)-이다. 몇 가지 양태에서, T는 -CH₂-, -CF₂-, -C(CH₃)₂-,

이다. 보다 바람직하게는, T는 -CH₂-, -CF₂-, 또는 -C(CH₃)₂-이다. 몇 가지 양태에서, T는 -CH₂-이다. 또는, T는 -CF₂-이 다. 또는, T는 -C(CH₃)₂-이다.In some embodiments, T is -CH _2- , -CH ₂ CH _2- , -CF _2- , -C (CH ₃ ) _2- , -C (O)-,

, -C (phenyl) _2- , -B (OH)-, and -CH (OEt)-. In some embodiments, T is -CH _2- , -CF _2- , -C (CH ₃ ) _2- ,

Or -C (phenyl) _2- . In another embodiment, T is -CH ₂ H _2- , -C (O)-, -B (OH)-, and -CH (OEt)-. In some embodiments, T is -CH _2- , -CF _2- , -C (CH ₃ ) _2- ,

to be. More preferably, T is -CH _2- , -CF _2- , or -C (CH ₃ ) _2- . In some embodiments, T is —CH ₂ —. Or T is -CF _2- . Or T is -C (CH ₃ ) _2- .

In some embodiments, R ₁ ′ and R ₁ ″ are each hydrogen. In some embodiments, R ₁ ′ and R ₁ ″ are each independently —Z ^A R ₅ , wherein Z ^A is each independently bonded or optionally substituted Branched or linear C _1-6 aliphatic chains, up to two carbon units of Z ^A are optionally independently -CO-, -CS-, -CONR ^A- , -CONR ^A NR ^A- , -CO _2- , -OCO-, -NR ^A CO _2- , -O-, -NR ^A CONR ^A- , -OCONR ^A- , -NR ^A NR ^A- , -NR ^A CO-, -S-, -SO-, -SO _2- , -NR ^A- , -SO ₂ NR ^A- , -NR ^A SO _2- , or -NR ^A SO ₂ NR ^A- . R ₅ is each independently R ^A , halo, —OH, —NH ₂ , —NO ₂ , —CN, —CF ₃ , or —OCF ₃ . R ^A is each independently an optionally substituted group selected from C _1-8 aliphatic groups, alicyclic, heteroalicyclic, aryl and heteroaryl.

In some embodiments, R ₁ ′ is H, C _1-6 aliphatic, halo, CF ₃ , CHF ₂ , —O (C _1-6 aliphatic), C 3 -C 5 cycloalkyl, or C ₄ containing one oxygen atom. -C ₆ heterocycloalkyl. In some embodiments, R ₁ ′ is H, methyl, ethyl, i -propyl, t -butyl, F, Cl, CF ₃ , CHF ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O- ( i -propyl) And -O- ( t -butyl). More preferably, R ₁ ′ is H. Or R ₁ ′ is methyl. Or ethyl. Or CF ₃ .

In certain embodiments, R ₁ "is selected from the group consisting of H, C _{1 -6} aliphatic, halo, CF _3, CHF _2, and -O (C _{1 -6} aliphatic). In certain embodiments, R _1" is H , Methyl, ethyl, i -propyl, t -butyl, F, Cl, CF ₃ , CHF ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O- ( i -propyl) and -O- ( t -butyl) It is selected from the group consisting of. More preferably, R ₁ "is H. Or, R ₁ " is methyl. Or ethyl. Or CF ₃ .

In some embodiments, R ^D1 is bonded to a 3 "or 4" carbon, and -Z ^D R ₉ , wherein Z ^D is each independently a branched or linear C _1-6 aliphatic chain bonded or optionally substituted, and Z ^D Up to two carbon units are optionally independently -CO-, -CS-, -CONR ^E- , -CONR ^E NR ^E- , -CO _2- , -OCO-, -NR ^E CO _2- , -O- , -NR ^E CONR ^E- , -OCONR ^E- , -NR ^E NR ^E- , -NR ^E CO-, -S-, -SO-, -SO _2- , -NR ^E- , -SO ₂ NR ^E- , -NR ^E SO _2- , or -NR ^E SO ₂ NR ^E- . In some embodiments, Z ^D is an independently bonded or optionally substituted branched or linear C _1-6 aliphatic chain, and one carbon unit of Z ^D is —CO—, —SO—, —SO ₂ —, —COO— , -OCO-, -CONR ^E- , -NR ^E CO-, NR ^E CO _2- , -O-, -NR ^E SO _2- , or -SO ₂ NR ^E- . In some embodiments, one carbon unit of Z ^D is optionally replaced by —CO—. Or optionally substituted by -SO-. Or, optionally substituted by -SO _2- . Or optionally substituted by -COO-. Or optionally substituted by -OCO-. Or, optionally substituted by -CONR ^E- . Or optionally substituted by -NR ^E CO-. Or, optionally substituted by -NR ^E CO _2- . Or optionally substituted by -O-. Or, optionally substituted by -NR ^E SO _2- . Or, optionally substituted by -SO ₂ NR ^E- .

In some embodiments, R ₉ is hydrogen, halo, —OH, —NH ₂ , —CN, —CF ₃ , —OCF ₃ , or C _1-6 aliphatic, C _3-8 cycloaliphatic, 3-8 membered complex Optionally substituted group selected from the group consisting of cyclic, C _6-10 aryl, and 5-10 membered heteroaryl. In some instances, R ₉ is hydrogen, F, Cl, -OH, -CN, -CF ₃ , or -OCF ₃ . In some embodiments, R ⁹ is C _1-6 aliphatic, C _3-8 alicyclic, 3-8 membered heteroalicyclic, C _6-10 aryl, and 5-10 membered heteroaryl [each of R ^E , oxo, Halo, —OH, —NR ^E R ^E , —OR ^E , —COOR ^E , and —CONR ^E R ^E , optionally substituted by one or two substituents independently. In some instances, R ₉ is oxo, F, Cl, methyl, ethyl, i -propyl, t -butyl, -CH ₂ OH, -CH ₂ CH ₂ OH, -C (O) OH, -C (O) 1 independently selected from the group consisting of NH ₂ , —CH ₂ O (C _1-6 alkyl), —CH ₂ CH ₂ O (C _1-6 alkyl), and —C (O) (C _1-6 alkyl) Optionally substituted by two substituents.

In one embodiment, R ₉ is hydrogen. In some embodiments, R ₉ is C _{1 -6} straight or branched chain alkyl or C _{2 -6} straight or branched chain group consisting of alkenyl; wherein the alkyl or alkenyl is R ^E, oxo, halo, -OH, -NR ^E R Optionally substituted with one or two substituents independently selected from the group consisting of ^E , -OR ^E , -COOR ^E , and -CONR ^E R ^E.

In other embodiments, R ₉ is substituted on one or two substituents independently selected from the group consisting of R ^E , oxo, halo, -OH, -NR ^E R ^E , -OR ^E , -COOR ^E , and -CONR ^E R ^E is a C _{3 -8} cycloaliphatic optionally substituted. Examples of cycloaliphatic include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

를 포함한다.In another embodiment, R ₉ is a 3-8 membered heterocyclic having 1 or 2 heteroatoms independently selected from the group consisting of O, NH, NR ^E and S, wherein the heterocyclic is R ^E , oxo, halo , -OH, -NR ^E R ^E , -OR ^E , -COOR ^E , and -CONR ^E R ^E are optionally substituted with one or two substituents independently selected from the group. 3-8 membered heterocyclics are not intended to be limited to these,

.

를 포함한다.In some other embodiments, R ₉ is optionally substituted 5-8 membered heteroaryl having 1 or 2 ring atoms independently selected from the group consisting of O, S, and NR ^E. Examples of 5-8 membered heteroaryls include, but are not limited to,

.

In some embodiments, R ^D1 and R ^D2 are optionally substituted 4-8 membered saturation having 0 to 2 ring atoms independently selected from the group consisting of O, NH, NR ^E and S together with the carbon to which they are attached, To form partially unsaturated or aromatic rings.

을 포함한다.Examples of R ^D1 and R ^D2 formed with phenyl containing 3 ″ and 4 ″ carbon atoms are not intended to be limiting,

.

In some embodiments, R ^D2 is H, R ^E , halo, -OH,-(CH ₂ ) _r NR ^E R ^E ,-(CH ₂ ) _r -OR ^E , -SO ₂ -R ^E , -NR ^E -SO ₂ -R ^E , -SO ₂ NR ^E R ^E , -C (O) R ^E , -C (O) OR ^E , -OC (O) OR ^E , -NR ^E C (O) OR ^E and -C ( O) NR ^E R ^E wherein r is 0, 1 or 2. In other embodiments, R ^D2 is H, C _1-6 aliphatic, halo, -CN, -NH ₂ , -NH (C _1-6 aliphatic), -N (C _1-6 aliphatic) ₂ , -CH ₂ -N (C _1-6 aliphatic) ₂ , -CH ₂ -NH (C _1-6 aliphatic), -CH ₂ NH ₂ , -OH, -O (C _1-6 aliphatic), -CH ₂ OH, -CH _2- O (C _1-6 aliphatic), -SO ₂ (C _1-6 aliphatic), -N (C _1-6 aliphatic) -SO ₂ (C _1-6 aliphatic), -NH-SO ₂ (C _1-6 Aliphatic), -SO ₂ NH ₂ , -SO ₂ NH (C _1-6 aliphatic), -SO ₂ N (C _1-6 aliphatic) ₂ , -C (O) (C _1-6 aliphatic), -C ( O) O (C _1-6 aliphatic), -C (O) OH, -OC (O) O (C _1-6 aliphatic), -NHC (O) (C _1-6 aliphatic), -NHC (O) O (C _1-6 aliphatic), -N (C _1-6 aliphatic) C (O) O (C _1-6 aliphatic), -C (O) NH ₂ , and -C (O) N (C _{1- 6} aliphatic) ₂ ; In some instances, R ^D2 is H, C _1-6 aliphatic, halo, -CN, -NH ₂ , -CH ₂ NH ₂ , -OH, -O (C _1-6 aliphatic), -CH ₂ OH,- SO ₂ (C _1-6 aliphatic), -NH-SO ₂ (C _1-6 aliphatic), -C (O) O (C _1-6 aliphatic), -C (O) OH, -NHC (O) ( C _1-6 aliphatic), -C (O) NH ₂ , -C (O) NH (C _1-6 aliphatic), and -C (O) N (C _1-6 aliphatic) ₂ . For example, R ^D2 is H, methyl, ethyl, n-propyl, i-propyl, t-butyl, F, Cl, CN, -NH ₂ , -CH ₂ NH ₂ , -OH, -OCH ₃ , -O -Ethyl, -O- (i-propyl), -O- (n-propyl), -CH ₂ OH, -SO ₂ CH ₃ , -NH-SO ₂ CH ₃ , -C (O) OCH ₃ , -C (O) OCH ₂ CH ₃ , -C (O) OH, -NHC (O) CH ₃ , -C (O) NH ₂ , and -C (O) N (CH ₃ ) ₂ . In one embodiment, R ^D2 is hydrogen. In another embodiment, R ^D2 is methyl. Or R ^D2 is ethyl. Or R ^D2 is F. Or R ^D2 is Cl. Or -OCH ₃ .

In one embodiment, the present invention provides a compound of formula VIaa or VIab.

In the above formulas VIaa and VIab,

T, R ^D1 , R ^D2 and R ₁ ′ are as defined above.

In one embodiment, T is -CH _2- , -CF _2- , or -C (CH ₃ ) _2- .

In one embodiment, R ₁ ′ contains H, C _1-6 aliphatic, halo, CF ₃ , CHF ₂ , —O (C _1-6 aliphatic), C ₃ -C ₅ cycloalkyl, or one oxygen atom Is selected from the group consisting of C ₄ -C ₆ heterocycloalkyl. Exemplary embodiments are H, methyl, ethyl, i -propyl, t -butyl, F, Cl, CF ₃ , CHF ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -O- ( i -propyl), -O- ( t -butyl), cyclopropyl, or oxetanyl. More preferably, R ₁ ′ is H. Or R ₁ ′ is methyl. Or ethyl. Or CF ₃ . Or oxetanyl.

In one embodiment, R ^D1 is Z ^D R ₉ [wherein, Z ^D is _{CONH, NHCO, SO 2 NH,} SO 2 N (C 1 -6 _{alkyl), NHSO 2, CH 2 NHSO} 2, CH 2 N (CH ₃ ) SO ₂ , CH ₂ NHCO, COO, SO ₂ , or CO. In one embodiment, R ^D1 is Z ^D R ₉ [wherein, Z ^D is _{CONH, SO 2 NH, SO 2} N (C 1 -6 _{alkyl), CH 2 NHSO 2, CH} 2 N (CH 3) SO 2, CH ₂ NHCO, COO, SO ₂ , or CO.

In one embodiment, Z ^D is COO and R ₉ is H. In one embodiment, Z ^D is COO, R ₉ is a straight or branched C _{1 -6} aliphatic group optionally substituted. In one embodiment, Z ^D is COO and, R ₉ is an optionally substituted straight or branched C _{1 -6} alkyl. In one embodiment, ^D is Z is COO, R ₉ is a C _{1 -6} alkyl. In one embodiment, Z ^D is COO and R ₉ is methyl.

In one embodiment, Z ^D is CONH and R ₉ is H. In one embodiment, Z is CONH and ^D, R ₉ is a straight or branched C _{1 -6} aliphatic group optionally substituted. In one embodiment, ^D is Z is CONH, R ₉ is a straight or branched C _{1 -6} alkyl. In one embodiment, Z ^D is CONH and R ₉ is methyl. In one embodiment, Z is CONH and ^D, R ₉ is an optionally substituted straight or branched C _{1 -6} alkyl. In one embodiment, Z ^D is CONH and R ₉ is 2- (dimethylamino) -ethyl.

In certain embodiments, Z ^D is CH ₂ NHCO, R ₉ is an optionally substituted straight or branched C _{1 -6} aliphatic or optionally substituted alkoxy. In certain embodiments, Z ^D is CH ₂ NHCO and, R ₉ is halo, oxo, hydroxyl a chamber optionally substituted straight or branched C _{1 -6} alkyl, or an aliphatic, cyclic, aryl, heteroaryl, alkoxy, amino, carboxyl Or an optionally substituted group selected from carbonyl. In one embodiment, Z ^D is CH ₂ NHCO and R ₉ is methyl. In one embodiment, Z ^D is CH ₂ NHCO and R ₉ is CF ₃ . In one embodiment, Z ^D is CH ₂ NHCO and R ₉ is t-butoxy.

In one embodiment, Z ^D is SO ₂ NH and R ₉ is H. In certain embodiments, Z ^D is SO ₂ NH, R ₉ is a straight or branched C _{1 -6} aliphatic group optionally substituted. In certain embodiments, Z ^D is SO ₂ NH and, R ₉ is halo, oxo, hydroxyl, optionally substituted straight or branched C _{1 -6} alkyl, or C _{1 -6} aliphatic, 3-8 won cyclic, C _{6 -10} aryl, 5-8 membered heteroaryl, alkoxy, amino, amido, carboxyl and carbonyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is methyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is ethyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is i -propyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is t -butyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is 3,3-dimethylbutyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH ₂ CH ₂ OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH (CH ₃ ) CH ₂ OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH ₂ CH (CH ₃ ) OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH (CH ₂ OH) ₂ . In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH ₂ CH (OH) CH ₂ OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH ₂ CH (OH) CH ₂ CH ₃ . In one embodiment, Z ^D is SO ₂ NH and R ₉ is C (CH ₃ ) ₂ CH ₂ OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH (CH ₂ CH ₃ ) CH ₂ OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH ₂ CH ₂ OCH ₂ CH ₂ OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is C (CH ₃ ) (CH ₂ OH) ₂ . In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH ₂ CH (OH) CH ₂ C (O) OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH ₂ CH ₂ N (CH ₃ ) ₂ . In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH ₂ CH ₂ NHC (O) CH ₃ . In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH (CH (CH ₃ ) ₂ ) CH ₂ OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH (CH ₂ CH ₂ CH ₃ ) CH ₂ OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is 1-tetrahydrofuryl-methyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is furylmethyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is (5-methylfuryl) -methyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is 2-pyrrolidinylethyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is 2- (1-methylpyrrolidinyl) -ethyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is 2- (4-morpholinyl) -ethyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is 3- (4-morpholinyl) -propyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is C (CH ₂ CH ₃ ) (CH ₂ OH) ₂ . In one embodiment, Z ^D is SO ₂ NH and R ₉ is 2- (1 H -imidazol-4-yl) ethyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is 3- (1 H -imidazol-1-yl) -propyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is 2- (2-pyridinyl) -ethyl.

In certain embodiments, Z ^D is SO ₂ NH, R ₉ is a C _{1 -6} aliphatic group optionally substituted. In some examples, Z ^D is SO ₂ NH, R ₉ is optionally substituted C _{1 -6} cycloalkyl. In some examples, Z ^D is SO ₂ NH, R ₉ is a C _{1 -6} cycloalkyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is cyclobutyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is cyclopentyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is cyclohexyl.

In certain embodiments, Z ^D is SO ₂ N (C _{1 -6} alkyl), R ₉ is a straight or branched C _{1 -6} aliphatic or an optionally substituted cycloaliphatic, optionally substituted. In certain embodiments, Z ^D is SO ₂ N (C _{1 -6} alkyl), R ₉ is a straight or branched C _{1 -6} aliphatic group optionally substituted. In certain embodiments, Z ^D is SO ₂ N (C _{1 -6} alkyl), R ₉ is a straight or branched alkenyl optionally substituted with C _{1 -6} alkyl or an optionally substituted straight or branched C _{1 -6} al. In one embodiment, Z ^D is SO ₂ N (CH ₃ ) and R ₉ is methyl. In one embodiment, Z ^D is SO ₂ N (CH ₃ ) and R ₉ is n-propyl. In one embodiment, Z ^D is SO ₂ N (CH ₃ ) and R ₉ is n-butyl. In one embodiment, Z ^D is SO ₂ N (CH ₃ ) and R ₉ is cyclohexyl. In one embodiment, Z ^D is SO ₂ N (CH ₃ ) and R ₉ is allyl. In one embodiment, Z ^D is SO ₂ N (CH ₃ ) and R ₉ is CH ₂ CH ₂ OH. In one embodiment, Z ^D is SO ₂ N (CH ₃ ) and R ₉ is CH ₂ CH (OH) CH ₂ OH. In one embodiment, Z ^D is SO ₂ N (CH ₂ CH ₂ CH ₃ ) and R ₉ is cyclopropylmethyl.

In one embodiment, Z ^D is CH ₂ NHSO ₂ and R ₉ is methyl. In one embodiment, Z ^D is CH ₂ N (CH ₃ ) SO ₂ and R ₉ is methyl.

을 포함한다.In certain embodiments, Z is ^D is SO _2, R ₉ is optionally substituted C _{1 -6} linear or branched aliphatic or nitrogen, oxygen, sulfur, one, two or three ring members selected from the group consisting of SO ₂ and SO Optionally substituted 3-8 membered heterocyclic. In certain embodiments, Z ^D is SO _2, R ₉ is a straight or branched C _{1 -6} alkyl or by 1, 2 or 3 of oxo, halo, optionally substituted 3-8 restore possession hwanjok hydroxyl, or C _1-6 is a group selected from optionally substituted aliphatic, carbonyl, amino, and carboxy. In one embodiment, Z ^D is SO ₂ and R ₉ is methyl. In some embodiments, Z ^D is SO ₂ , An example of R ₉

.

In certain embodiments, R ^D2 is H, hydroxyl, halo, C _{1 -6} alkyl, C _{1 -6} alkoxy, C _{3 -6} cycloalkyl, or NH _2. In some examples, R ^D2 is H, halo, C _{1 -4} alkyl or C _{1 -4} alkoxy. Examples of R ^D2 include H, F, Cl, methyl, ethyl, and methoxy.

In some embodiments, the present invention provides a compound of formula (Iaa) or (Iab) or a pharmaceutically acceptable salt thereof.

In the above formulas Iaa and Iab,

R ₁ , R ₂ , R ₃ , R ' ₃ , R ₄ and n are as defined above.

In some embodiments, R ₁ is optionally substituted aryl. In some examples, R ₁ is 1, 2, or 3 halo, OH, -O (C _{1 -6} aliphatic), amino, C _{1 -6} aliphatic, C _{3 -7} cycloaliphatic, 3-8 restore possession a hwanjok, C _{6 -10} aryl, or 5-8 membered heteroaryl optionally substituted by phenyl. In some embodiments, R ₁ is phenyl optionally substituted with alkoxy, halo, or amino. In one embodiment, R ₁ is phenyl. In one embodiment, R ₁ is phenyl substituted with Cl, methoxy, ethoxy, or dimethylamino.

In some embodiments, R ₂ is hydrogen. In some embodiments, R ₂ is an optionally substituted C _{1 -6} aliphatic.

In some aspects, R _3, R _'3, and to which they are attached carbon atom to form an optionally substituted C _{3 -8} cycloaliphatic, or an optionally substituted 3-8 restore possession hwanjok. In some aspects, R _3, R _'3 and who they are carbon atoms bonded to form an optionally substituted C _{3 -8} cycloalkyl. In one example, R ₃ , R ′ ₃ and the carbon atoms to which they are attached are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, each of which is optionally substituted. In one example, R ₃ , R ′ ₃ and the carbon atoms to which they are attached are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In some instances, R ₃ , R ′ ₃ and the carbon atom to which they are attached are cyclopropyl.

(여기서, T는 위에서 정의한 바와 같다)이다. 몇 가지 예에서, T는 -CH₂-이다.In some embodiments, R ₄ is optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, R ₄ is optionally substituted phenyl. In some embodiments, R ₄ is phenyl fused to 3, 4, 5 or 6 membered heterocyclic having 1, 2 or 3 rings selected from oxygen, sulfur and nitrogen. In some embodiments, R ₄ is

Where T is as defined above. In some instances, T is -CH _2- .

Alternative embodiments of R ₁ , R ₂ , R ₃ , R ' ₃ , R ₄ and n in Formula Iaa or Iab are as defined for Formula I, Ia and embodiments thereof.

Exemplary compounds of the present invention include, but are not limited to, those illustrated in Table 1 below.

Synthetic scheme

The compounds of the present invention can be prepared by known methods or as illustrated in the examples. In one example where R ₁ is aryl or heteroaryl, the compounds of the present invention can be prepared as described in Scheme I.

a) 50% NaOH, XR ₃ -R ' ₃ -Y, BTEAC; X, Y = leaving group; b) SOCl ₂ , DMF; c) pyridine; d) R ₁ -B (OR) ₂ , Pd (dppf) Cl ₂ , K ₂ CO ₃ , DMF, H ₂ O

a) Pd (PPh ₃ ) ₄ , CO, MeOH; b) LiAlH ₄ , THF; c) SOCl ₂ ; d) NaCN; e) NBS or NCS, AIBN, CX ₄ (X = Br or Cl)

a) pyridine, DCM; b) R ₁ -B (OR) ₂ , Pd (dppf) Cl ₂ , K ₂ CO ₃ , DMF, H ₂ O

a) pyridine, DCM; b) R ₁ -B (OR) ₂ , Pd (dppf) Cl ₂ , K ₂ CO ₃ , DMF, H ₂ O

Referring to Scheme I, nitrile (i) is alkylated with dihalo-aliphatic in the presence of a base such as 50% sodium hydroxide and optionally in the presence of a phase transfer agent such as benzyltriethylammonium chloride (BTEAC). Hydrolysis yields the corresponding alkylated nitrile (not shown) which produces acid (ii) (step a). Compound (ii) is converted to acid chloride (iii) with a suitable agent, for example thionyl chloride / DMF. The reaction of acid chloride (iii) with aminopyridine (iv), where X is halo, gives amide (v) (step c). Amide (v) of an optionally substituted boronic acid derivative with a catalyst, for example palladium acetate or dichloro- [1,1-bis (diphenylphosphino) ferrocene] palladium (II) (Pd (dppf) Cl ₂ ) Reaction in presence provides a compound of the invention wherein R ₁ is aryl, heteroaryl or cycloalkenyl (step d). Boronic acid derivatives (vi) are commercially available or may be prepared by known methods such as, for example, reaction of aryl bromide with diborane ester in the presence of a coupling agent such as palladium acetate as described in the Examples.

(여기서, X는 할로이고, Q는 C_1-6 지방족, 아릴, 헤테로아릴, 또는 3 내지 10원 지환족 또는 복소지환족이다)과 같은 적합하게 치환된 아미노피리딘을 사용하여 반응식 I의 단계 a, b 및 c에 기재된 바와 같이 제조할 수 있다.In another example where one R ₁ is aryl and another R ₁ is aliphatic, alkoxy, cycloaliphatic, or heteroalicyclic, a compound of the invention is used as a substituent to aminopyridine (iv)

Step a of Scheme I using suitably substituted aminopyridine such as X is halo and Q is C _1-6 aliphatic, aryl, heteroaryl, or 3 to 10 membered alicyclic or heteroalicyclic , b and c can be prepared as described.

Formulations, Administration and Uses

Pharmaceutically acceptable compositions

Accordingly, in another aspect of the present invention, there is provided a pharmaceutically acceptable composition comprising any of the compounds described herein and optionally comprising a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, the composition optionally further comprises one or more additional therapeutic agents.

It will also be appreciated that certain compounds of the present invention may exist in free form for treatment, or if necessary, in a pharmaceutically acceptable derivative or prodrug thereof. In accordance with the present invention, pharmaceutically acceptable derivatives or prodrugs are agents that are not intended to be limited thereto, but may provide, directly or indirectly, the compounds described herein, or metabolites or residues thereof, when administered to a patient in need thereof. Pharmaceutically acceptable salts, esters, salts of such esters, and other adducts or derivatives.

As used herein, the term “pharmaceutically acceptable salts” is suitable and appropriate for use in contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., within the scope of safe medical judgment. Refers to the salt corresponding to the benefit / risk ratio. Pharmaceutically acceptable salts are salts of any non-toxic salts or esters of the compounds of the invention, which when administered to a receptor can provide directly or indirectly a compound of the invention, or a inhibitory active metabolite or residue thereof. Even means.

Pharmaceutically acceptable salts are well known in the art. See, eg, SM Berge, et al., J. Pharmaceutical Sciences , 1977, 66 , 1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid. Or a salt of an amino group formed with malonic acid, or is formed using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropio Nate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydro Roxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, maleate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxal Latex, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, piclay Include, pivalate, propionate, stearate, succinate, sulfate, tartrate, such as thiocyanate, p- toluenesulfonate, undecanoate, valerate salts. Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternization of any basic nitrogen containing group of the compounds described herein. Water- or oil-soluble or dispersible products can be obtained by this quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts, if necessary, are non-toxic ammoniums formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates, Quaternized ammonium and amine cations.

As described above, the pharmaceutically acceptable compositions of this invention, as used herein, may comprise any and all solvents, diluents or other liquid vehicles, dispersions or suspension aids, surfaces, suitable for the particular dosage form desired. And pharmaceutically acceptable carriers, adjuvants or vehicles, including active agents, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like. Remington: The Science and Practice of Pharmacy , 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology , eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference, discloses various carriers used to formulate pharmaceutically acceptable compositions and known for the preparation thereof. Described techniques are described. For example, by creating any unnecessary biological action or otherwise interacting with any other component (s) of the pharmaceutically acceptable composition in a deleterious manner, any conventional carrier medium is incompatible with the compounds of the present invention. Except in the cases, the use thereof is considered to be within the scope of the present invention. Some examples of materials that can act as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer materials, eg For example, phosphates, glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, for example protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloids Acidic silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, parent fats, sugars such as lactose, glucose and sucrose; Starch such as corn starch and potato starch; Cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Tragacanth powder; Malt; gelatin; talc; Excipients such as cocoa butter and suppository waxes; Oils such as peanut oil, cottonseeds; Safflower oil; Sesame oil; olive oil; Corn oil and soybean oil; Glycols such as propylene glycol or polyethylene glycol; Esters such as ethyl oleate and ethyl laurate; Agar; Buffers such as magnesium hydroxide and aluminum hydroxide; Alginic acid; Pyrogen-free distilled water; Isotonic saline; Ringer's solution; Ethyl alcohol and phosphate buffer solutions, as well as non-toxic miscible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coatings, sweeteners, flavors and flavorings, Preservatives and antioxidants may also be present in the compositions, as determined by the formulator.

Use of compounds and pharmaceutically acceptable compositions

In another aspect, the present invention provides a method for treating a condition, disease or disorder related to ABC transporter activity. In certain embodiments, the present invention comprises administering a composition comprising a compound of Formulas (I), (II), (III), (IV), Va, Vb, Ia, Iaa, and Iab to a subject in need thereof, preferably a mammal. And methods of treating a condition, disease or disorder associated with a lack of ABC transporter activity.

In certain preferred embodiments, the invention provides a method of administering to a mammal an effective amount of a compound comprising Formulas I, II, III, IV, Va, Vb, Ia, Iaa, and Iab, or a composition comprising a preferred embodiment thereof as described above. Cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolytic deficiency, eg, protein C deficiency, type 1 hereditary angioedema, lipid processing deficiency, eg, familial hypercholesterolemia, type 1 kilo Micronemia, mubetalipoproteinemia, lysosomal storage diseases, such as I-cell disease / caustic huller disease, mucopolysaccharide, sandhof / Tey-Sarks, type II Krigler-Nazar, multi-occurrence endocrine disorders Hyperinsulinemia, diabetes mellitus, laron dwarfism, myeloperoxidase deficiency, primary parathyroidism, melanoma, type 1 glycanolysis CDG, hereditary emphysema, congenital hyperthyroidism, incomplete osteosarcoma, hereditary hypofibrosis Microcytopathy, ACT deficiency, diabetes insipidus (DI), neurophagosy insipidus, neoplastic diabetes insipidus, Sharco-Maritus syndrome, Perijaeus-Mertzvacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, progressive nucleus palsy, Pick's disease, some polyglutamine neurological disorders such as Huntington's disease, type I spinal cord ataxia, spinal and bulbous muscular dystrophy, plaque nucleus cholangiotrophic atrophy, and myotonic dysplasia As well as cavernous encephalopathy, such as hereditary Creutfeldt-Jakob disease (due to prion protein processing defects), Fabry disease, Straussler-Shinker disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease ( COPD), dry eye syndrome, and Suegren's syndrome.

According to a preferred alternative embodiment, the present invention comprises administering to a mammal an effective amount of a compound comprising Formulas I, II, III, IV, Va, Vb, Ia, Iaa and Iab, or a composition comprising a preferred embodiment thereof as described above. It includes, it provides a method of treating cystic fibrosis.

According to the present invention, an "effective amount" of a compound or pharmaceutically acceptable composition is defined as cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolytic deficiency, such as protein C deficiency, type 1 hereditary angioedema, lipid treatment Deficiency, eg, familial hypercholesterolemia, type 1 kilomicronemia, mubetalipoproteinemia, lysosomal storage diseases, eg, I-cell disease / caustic huler disease, mucopolysaccharide, sandhof / tei Sarks, Crigler-Najjar type II, multi-occurrence endocrine disorders / hyperinsulinemia, diabetes, laron dwarfism, myeloperoxidase deficiency, primary parathyroidism, melanoma, type 1 glycan Degraded CDG, Hereditary Emphysema, Congenital Hypothyroidism, Incomplete Osteogenesis, Hereditary Hypofibrosis, ACT Deficiency, Diabetes Insipidus (DI), Neurophagy Insipidus, Myogenic Insipidosis, Sharco-Maritus Syndrome, Perizaou Mertzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive nuclear palsy, Pick's disease, some polyglutamine neurological disorders such as Huntington's disease, type I spinal cord cerebellum Ataxia, spinal and bulbous muscular dystrophy, alveolar nucleus cholangiotrophic atrophy, and myotonic dystrophy such as spongy encephalopathy such as hereditary Creutfeldt-Jakob disease, Fabry disease, Straussler-Shinker disease, An amount effective to treat or alleviate the severity of one or more of secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye syndrome, and Ssugren syndrome.

Compounds and compositions according to the methods of the invention may be cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolytic deficiency, eg protein C deficiency, type 1 hereditary angioedema, lipid processing deficiency, eg familiality. Hypercholesterolemia, type 1 micromicronemia, mubetalipoproteinemia, lysosomal storage diseases, such as I-cell disease / caustic huler disease, mucopolysaccharide, sandhof / Tey-Sarks, type II Krigler Nazar, multi-occurrence endocrine disorders / hyperinsulinemia, diabetes mellitus, laron dwarfism, myeloperoxidase deficiency, primary hypothyroidism, melanoma, type 1 glycan degrading CDG, hereditary emphysema, congenital hyperthyroidism, incomplete osteosarcoma , Hereditary hypofibrinemia, ACT deficiency, diabetes insipidus (DI), neurophagosy insipidus, neoplastic insipidus, Sharco-Maritus syndrome, Perissaeus-Mertzvacher disease, neurodegenerative diseases, for example, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive nuclear palsy, Pick's disease, some polyglutamine neurological disorders such as Huntington's disease, type I spinal cord ataxia, spinal and bulbous muscular dystrophy, spontaneous nucleus cholangiotropia Atrophy, and myotonic dysplasia, as well as cavernous encephalopathy such as hereditary Creutfeldt-Jakob disease, Fabry disease, Straussler-Shinker disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), Any amount and any route of administration effective for treating or alleviating the severity of one or more of dry eye syndromes and Sjogren's syndrome can be administered.

The exact amount required varies from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular agent, and the mode of administration thereof. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dose. As used herein, the expression “dosage unit form” refers to physically discrete units of formulation suitable for the patient to be treated. However, it will be understood that the total daily usage of the compounds and compositions of the present invention will be determined with the attendance of a physician within the scope of safe medical judgment. Specific effective dose levels for any particular patient or organism include the disorder being treated and the severity of the disorder; The activity of the specific compound used; The particular composition used; Age, weight, general health, sex and diet of the patient; The time of administration, route of administration, and rate of excretion of the specific compound employed; Treatment period; It depends on various factors, including agents used in combination or coincidental with the specific compound employed, and factors well known in the medical arts. The term "patient" as used herein means an animal, preferably a mammal, most preferably a human.

The pharmaceutically acceptable compositions of the present invention may be used orally, rectally, parenterally, intratracheally, intravaginally, intraperitoneally, topically (as powders, ointments or drops), oral cavity, depending on the severity of the infection being treated. Oral or nasal sprays. In certain embodiments, the compounds of the present invention may be administered orally or parenterally at a dosage level of about 0.01 to about 50 mg / kg, preferably about 1 to about 25 mg / kg, of the subject's body weight once or more than once daily. The desired therapeutic effect can be obtained.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms are inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl Alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofur Fatty acid esters of furyl alcohol, polyethylene glycol and sorbitan, and mixtures thereof. In addition to inert carriers, oral compositions may also include auxiliaries such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, fragrances.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions or emulsions, eg, in 1,3-butanediol, in nontoxic parenterally acceptable diluents or solvents. Acceptable vehicles and solvents that may be employed include water, Ringer's solution, U.S.P. And isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally used as a solvent or suspending medium. For this purpose, blended nonvolatile oils including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

Injectable formulations may be sterilized, for example, by filtration through a bacterial retention filter or by incorporation of the sterilant in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use. have.

In order to sustain the effects of the compounds of the invention, it may often be desirable to delay the absorption of the compounds from subcutaneous or intramuscular injection. This can be accomplished using a liquid suspension of crystalline or amorphous material with poorly water solubility. The rate of absorption of the compound then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming microencapsule matrices of compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the particular polymer used, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably actives of the compounds of the invention in suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or solids at ambient temperature or liquid at body temperature and therefore melted in the rectum or vaginal cavity Suppositories that can be prepared by mixing with suppository waxes that release the compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is one or more inert pharmaceutically acceptable excipients or carriers such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starch, lactose, sucrose, Glucose, mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants, such as glycerol, d) disintegrants, eg Agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) Wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, stear Magnesium, solid polyethylene glycols, sodium lauryl and la are mixed sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise a buffer.

Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared using coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. Optionally, an opacifying agent may be included, and may also be in the form of a composition which uniquely or preferentially releases the active ingredient (s) in a particular delayed manner in certain parts of the intestine. Examples of insertion compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycols and the like.

In addition, the active compounds may be microencapsulated with one or more of the aforementioned excipients. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared using coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with one or more inert diluents such as sucrose, lactose or starch. In addition, such dosage forms may include, in conventional practice, additional materials other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also comprise a buffer. These may optionally comprise an opacifying agent and may also be in the form of a composition which only or preferentially releases the active ingredient (s) in a particular delayed manner in certain parts of the intestine. Examples of insertion compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservative or buffer may be required. Ophthalmic formulations, ear drops and eye drops are also contemplated as being within the scope of this invention. In addition, the present invention contemplates the use of transdermal patches that have the added benefit of controlled transport of the compound to the body. Such dosage forms are made by dissolving or dispensing the compound in the proper medium. In addition, absorption accelerators may be used to increase the flow rate of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

As generally described above, the compounds of the present invention are useful as modulators of ABC transporters. Thus, although not wishing to be bound by any theory, compounds and compositions are particularly useful for the overactivity or inactivity of ABC transporters to treat or alleviate the severity of a disease, condition or disorder associated with the disease, condition or disorder. If the overactivity or inactivity of the ABC transporter is associated with a particular disease, condition or disorder, the disease, condition or disorder may also be referred to as "ABC transporter mediated disease, condition or disorder". Thus, in another aspect, the present invention provides a method of treating or alleviating the severity of a disease, condition or disorder where the overactivity or inactivity of the ABC transporter is related to the disease state.

The activity of the compounds used in the present invention as modulators of ABC transporters can be assayed according to the methods generally described in the art and described in the Examples below.

In addition, the compounds and pharmaceutically acceptable compositions of the present invention can be used in combination therapy, i.e., before or before the performance of the compounds and the pharmaceutically acceptable compositions, concurrent with one or more other desired therapeutic or medical procedures. It will be appreciated that it can be administered later. Certain combinations of treatments (therapeutic agents or procedures) for use in combination therapy contemplate the combination of desired therapeutic agents and / or procedures with the therapeutic effect to be achieved. In addition, the treatments employed achieve the desired effect on the same disorder (eg, a compound of the invention may be administered simultaneously with another agent used to treat the same disorder) or they achieve different effects ( It will be appreciated that for example, side effects can be controlled. As used herein, additional therapeutic agents typically administered to treat or prevent a particular disease or condition are known as "suitable for the disease or condition being treated."

The amount of additional therapeutic agent present in the compositions of the present invention is no greater than the amount normally administered in a composition comprising such therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the composition will range from about 50 to 100% of the amount typically present in a composition comprising the additional therapeutic agent as the only therapeutically active agent.

The compounds of the present invention or pharmaceutically acceptable compositions thereof may be incorporated into implantable medical devices such as compositions for prosthetic, artificial valves, vascular grafts, stents and catheter coatings. Thus, in another aspect, the present invention includes a coating composition of an implantable device comprising a compound of the present invention as described above and a carrier suitable for coating the implantable device. In another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described above and a carrier suitable for coating the implantable device. Suitable paints and general methods of manufacturing coated implantable devices are described in U.S. Pat. Patent 6,099,562; 5,886,026; 5,886,026; And 5,304,121. Paints are typically biomiscible polymer materials such as hydrogel polymers, polymethylsildisiloxanes, polycaprolactones, polyethylene glycols, polylactic acid, ethylene vinyl acetate and mixtures thereof. The coating may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharide, polyethylene glycol, phospholipids or combinations thereof to impart controlled release properties to the composition.

Another aspect of the invention includes administering a compound of formula (I) or a composition comprising the compound to a patient or contacting a biological sample, wherein the ABC transporter of the biological sample or patient (eg, in vitro or in vivo) To modulate activity. As used herein, the term “biological sample” includes, but is not limited to, cell cultures or extracts thereof; Biopsied material obtained from a mammal or extracts thereof; And blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

Modulation of ABC transporter activity in biological samples is useful for a variety of purposes known to those skilled in the art. Examples of this purpose include, but are not limited to, the study of ABC transporters in biological and pathological phenomena and the comparative evaluation of new modulators for ABC transporters.

In another embodiment, a method of modulating the activity of an anion channel in vitro or in vivo, comprising contacting the anion channel with a compound of Formula I, II, III, IV, Va, Vb, Ia, Iaa and Iab This is provided. In a preferred embodiment, the anion channel is a chloride channel or bicarbonate channel. In another preferred embodiment, the anionic channel is a chloride channel.

According to an alternative embodiment, the invention comprises contacting a cell in need of an increase in the number of functional ABC transporters with a compound of formula I, II, III, IV, Va, Vb, Ia, Iaa and Iab. A method of increasing the number of functional ABC transporters is provided. As used herein, the term "functional ABC transporter" means an ABC transporter capable of transporting activity. In a preferred embodiment, the functional ABC transporter is CFTR.

In another preferred embodiment, the activity of the ABC transporter is determined by measuring the transmembrane voltage potential. The means for measuring the voltage potential across the membrane in a biological sample is by using methods known in the art, such as optical membrane potential assays or other electrophysiological methods.

Optical film potential assays are used to measure fluorescence changes, such as voltage / iron probe readers (VIPR). Gonzalez, J. E., K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4 (9): 431-439], Gonzalez, JE and RY Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells "Biophys J 69 (4): 1272-80; Gonzalez, J. E. and R. Y. Tsien (1997) "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4 (4): 269-77.

This voltage sensitive assay is based on the change in fluorescence resonance energy transfer (FRET) between the membrane solubility, the voltage sensitive dye DiSBAC ₂ (3) and the fluorescent phospholipid CC2-DMPE (which attaches to the outer leaflet of the plasma membrane and acts as a FTET donor). Shall be. The change in membrane potential (V _m ) redistributes negatively charged DiSBAC ₂ (3) across the plasma membrane and causes the amount of energy transfer from CC2-DMPE to change. Changes in fluorescence emission can be monitored using VIPR ^™ II, an integrated liquid handler and fluorescence detector designed to perform cell-based screens in 96-well or 384-well microtiter plates.

In another aspect, the invention provides a composition (i) comprising a compound of Formula (I), (II), (III), (IV), (Va), (B), (Ia), (Ia) and (Iab) or any one of the above embodiments, and a) a biological sample comprising And a kit for use in determining the activity of an ABC transporter or fragment thereof in a biological sample in vitro or in vivo, comprising in contact with and b) instructions for measuring the activity of the ABC transporter or fragment thereof. To provide. In one embodiment, the kit comprises: a) contacting the additional composition with a biological sample, b) measuring the activity of the ABC transporter or fragment thereof in the presence of the additional compound, and c) the ABC transporter in the presence of the additional compound. Further instructions are included for comparing the activity of to the density of the ABC transporter in the presence of a composition of the compounds of Formulas I, II, III, IV, Va, Vb, Ia, Iaa and Iab. In a preferred embodiment, the kit is used to measure the density of CFTR.

Manufacturing and Example

General process I: Carboxylic acid  Building blocks

Benzyltriethylammonium chloride (0.025 equiv) and a suitable dihalo compound (2.5 equiv) were added to the substituted phenyl acetonitrile. The mixture was heated at 70 ° C. and then 50% sodium hydroxide (10 equiv) was slowly added to the mixture. The reaction was stirred at 70 ° C. for 12-24 hours to fully form cycloalkyl moiety and then heated at 130 ° C. for 24-48 hours to allow complete conversion from nitrile to carboxylic acid. The dark brown / black reaction mixture was diluted with water and extracted three times with ethyl acetate and then dichloromethane each to remove the byproducts. The basic aqueous solution was acidified to less than pH 1 with concentrated hydrochloric acid and the precipitate which began to form at pH 4 was filtered and washed twice with 1M hydrochloric acid. The solid material was dissolved in dichloromethane and extracted twice with 1M hydrochloric acid and once with saturated aqueous sodium chloride solution. The organic solution was dried over sodium sulfate and evaporated to dryness to yield cycloalkylcarboxylic acid.

A. 1- Benzo [1,3] dioxol -5-yl- cyclopropanecarboxylic acid

Benzo [1,3] dioxol-5-acetonitrile (5.10 g, 31.7 mmol), 1-bromo-2-chloro-ethane (9.00 mL, 109 mmol) and benzyltriethylammonium chloride (0.181 g, 0.795 mmol ) Was heated at 70 ° C., and then 50% (wt./wt.) Aqueous sodium hydroxide (26 mL) was slowly added to the mixture. The reaction was stirred at 70 ° C. for 18 hours and then heated at 130 ° C. for 24 hours. The dark brown reaction mixture was diluted with water (400 mL) and extracted once with the same volume of ethyl acetate and once with the same volume of dichloromethane. The basic aqueous solution was acidified to less than pH 1 with concentrated hydrochloric acid, the precipitate was filtered off and washed with 1M hydrochloric acid. The solid material was dissolved in dichloromethane (400 mL) and extracted twice with the same volume of 1 M hydrochloric acid and once with a saturated aqueous solution of sodium chloride. The organic solution was dried over sodium sulfate and evaporated to dryness to give a white to slightly off-white solid (5.23 g, 80%). ESI-MS m / z calc .: 206.1. Found: 207.1 (M + 1) ⁺ . Retention time 2.37 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.07-1.11 (m, 2H), 1.38-1.42 (m, 2H), 5.98 (s, 2H), 6.79 (m, 2H), 6.88 (m, 1H ), 12.26 (s, 1 H).

General process II: Carboxylic acid  Building blocks

Sodium hydroxide (50% aqueous solution, 7.4 equiv) was slowly added to a mixture of suitable phenyl acetonitrile, benzyltriethylammonium chloride (1.1 equiv) and a suitable dihalo compound (2.3 equiv) at 70 ° C. The mixture was stirred overnight at 70 ° C. and the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to dryness to afford crude cyclopropanecarbonitrile, which was used directly in the next step.

The crude cyclopropanecarbonitrile was heated to reflux for 2.5 h in 10% aqueous sodium hydroxide (7.4 equiv). The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give cyclopropanecarboxylic acid as a white solid.

General process III: Carboxylic acid  Building blocks

B. 1- (2,2 -Difluoro - benzo [1,3] dioxol -5-yl) -cyclopropanecarboxylic acid

Step a: 2,2-difluoro-benzo [1,3] dioxol-5-carboxylic acid methyl ester

5-bromo-2,2-difluoro-benzo [1,3] dioxol (11.8 g, 50.0 mmol) in methanol (20 mL) containing acetonitrile (30 mL) and triethylamine (10 mL) ) And tetrakis (triphenylphosphine) palladium (0) [Pd (PPh ₃ ) ₄ , 5.78 g, 5.00 mmol] were stirred at 75 ° C. under carbon monoxide atmosphere (55 PSI) for 15 h (oil bath temperature). The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluoro-benzo [1,3] dioxol-5-carboxylic acid methyl ester (11.5 g), which was used directly in the next step.

Step b: (2,2-Difluoro-benzo [1,3] dioxol-5-yl) -methanol

Crude 2,2-difluoro-benzo [1,3] dioxol-5-carboxylic acid methyl ester (11.5 g) dissolved in 20 mL of anhydrous tetrahydrofuran (THF) was dissolved in dry THF (100 mL) at 0 ° C. It was slowly added to a suspension of lithium aluminum hydride (4.10 g, 106 mmol). The mixture was then allowed to warm to room temperature. After stirring for 1 hour at room temperature, the reaction mixture was cooled to 0 ° C. and treated with water (4.1 g) followed by sodium hydroxide (10% aqueous solution, 4.1 mL). The resulting slurry was filtered and washed with THF. The combined filtrates were evaporated to dryness and the residue was purified by silica gel column chromatography (2,2-difluoro-benzo [1,3] dioxol-5-yl) -methanol (7.2 g, 38 mmol, two 76%) for the step was obtained as a colorless oil.

Step c: 5-Chloromethyl-2,2-difluoro-benzo [l, 3] dioxol

Thionyl chloride (45 g, 38 mmol) of (2,2-difluoro-benzo [1,3] dioxol-5-yl) -methanol (7.2 g, 38 mmol) in dichloromethane (200 mL) at 0 ° C. It was added slowly to the solution. The resulting mixture was stirred overnight at room temperature and then evaporated to dryness. The residue was partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and dichloromethane (100 mL). The separated aqueous layer was extracted with dichloromethane (150 mL), the organic layer was dried over sodium sulfate, filtered and evaporated to dryness to afford 5-chloromethyl-2,2-difluoro-benzo [1,3]. ] Dioxol (4.4 g) was obtained and used directly in the next step.

Step d: (2,2-Difluoro-benzo [1,3] dioxol-5-yl) -acetonitrile

A mixture of crude 5-chloromethyl-2,2-difluoro-benzo [1,3] dioxol (4.4 g) and sodium cyanide (1.36 g, 27.8 mmol) in dimethyl sulfoxide (50 mL) was added at room temperature. Stir overnight. The reaction mixture was poured into ice and extracted with ethyl acetate (300 mL). Dry the organic layer with sodium sulfate and evaporate to dryness to afford crude (2,2-difluoro-benzo [1,3] dioxol-5-yl) -acetonitrile (3.3 g), which is the next step Used directly at

Step e: 1- (2,2-Difluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarbonitrile

Sodium hydroxide (50% aqueous solution, 10 mL) was added at 70 ° C. in crude (2,2-difluoro-benzo [1,3] dioxol-5-yl) -acetonitrile, benzyltriethylammonium chloride (3.00 g, 15.3 mmol) and 1-bromo-2-chloroethane (4.9 g, 38 mmol) were added slowly. The mixture was stirred at 70 ° C. overnight, then the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to dryness to afford crude 1- (2,2-difluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarbonitrile, which was then It was used directly in the step.

Step f: 1- (2,2-Difluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarboxylic acid

2.5 h of 1- (2,2-difluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarbonitrile (crude compound from last step) in 10% aqueous sodium hydroxide (50 mL) At reflux. The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give 1- (2,2-difluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarboxylic acid as a white solid (0.15 g, 1.6% for four steps). It was. ESI-MS m / z calc. 242.2, found 243.3 (M + 1) ⁺ ; ¹ H NMR (CDCl ₃ ) δ 7.14-7.04 (m, 2H), 6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H).

C. 2- (4 -chloro- 3 -methoxyphenyl ) acetonitrile

Step a: 1-chloro-2-methoxy-4-methyl-benzene

To a solution of 2-chloro-5-methyl-phenol (93 g, 0.65 mol) in CH ₃ CN (700 mL) was added CH ₃ I (111 g, 0.78 mol) and K ₂ CO ₃ (180 g, 1.3 mol). The mixture was stirred at 25 < 0 > C overnight. The solid was filtered off and the filtrate was evaporated in vacuo to give 1-chloro-2-methoxy-4-methyl-benzene (90 g, 89%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.22 (d, J = 7.8 Hz, 1 H), 6.74-6.69 (m, 2H), 3.88 (s, 3H), 2.33 (s, 3H).

Step b: 4-Bromomethyl-1-chloro-2-methoxy-benzene

To a solution of 1-chloro-2-methoxy-4-methyl-benzene (50 g, 0.32 mol) in CCl ₄ (350 mL) was added NBS (57.2 g, 0.32 mol) and AIBN (10 g, 60 mmol). The mixture was heated to reflux for 3 hours. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether / EtOAc = 20: 1) to give 4-bromomethyl-1-chloro-2-methoxy-benzene (69 g, 92%). Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33-7.31 (m, 1 H), 6.95-6.91 (m, 2 H), 4.46 (s, 2 H), 3.92 (s, 3 H).

Step c: 2- (4-chloro-3-methoxyphenyl) acetonitrile

To a solution of 4-bromomethyl-1-chloro-2-methoxy-benzene (68.5 g, 0.29 mol) in C ₂ H ₅ OH (90%, 500 mL) was added NaCN (28.5 g, 0.58 mol). . The mixture was stirred at 60 ° C. overnight. Ethanol was evaporated and the residue was dissolved in H ₂ O. The mixture was extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and purified by column chromatography on silica gel (petroleum ether / EtOAc 30: 1) to give 2- (4-chloro-3-methoxyphenyl) acetonitrile ( 25 g, 48%) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36 (d, J = 8 Hz, 1 H), 6.88-6.84 (m, 2H), 3.92 (s, 3H), 3.74 (s, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5.

D. (4 -Chloro- 3 -hydroxy - phenyl ) -acetonitrile

BBr ₃ (16.6 g, 66 mmol) was added slowly to a solution of 2- (4-chloro-3-methoxyphenyl) acetonitrile (12 g, 66 mmol) in DCM (120 mL) at -78 ° C. under N ₂ . The reaction temperature was slowly raised to room temperature. The reaction mixture was stirred overnight and then poured into ice water. The organic layer was separated and the aqueous layer extracted with DCM (40 mL × 3). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give (4-chloro-3-hydroxy-phenyl) -acetonitrile (9.3 g, 85%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.34 (d, J = 8.4 Hz, 1 H), 7.02 (d, J = 2.1 Hz, 1 H), 6.87 (dd, J = 2.1, 8.4 Hz, 1 H ), 5.15 (brs, 1 H), 3.72 (s, 2 H).

E. 1- (3- ( hydroxymethyl ) -4 -methoxyphenyl ) cyclopropanecarboxylic acid

Step a: 1- (4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester

Toluene-4-sulfonic acid monohydrate (2.5 g, 13 mmol) was added to a solution of 1- (4-methoxy-phenyl) -cyclopropanecarboxylic acid (50.0 g, 0.26 mol) in MeOH (500 mL) at room temperature. The reaction mixture was heated to reflux for 20 hours. Evaporate under vacuum to remove MeOH and EtOAc (200 mL) was added. The organic layer was washed with saturated aqueous NaHCO ₃ (100 mL), brine, dried over anhydrous Na ₂ SO ₄ , and evaporated in vacuo to give 1- (4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (53.5 g, 99%) was obtained. ¹ H NMR (CDCl _3, 400 MHz) δ 7.25-7.27 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H), 3.62 (s, 3H), 1.58 (m, 2H), 1.15 (m, 2H).

Step b: 1- (3-Chloromethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester

TiCl ₄ (8.30 g, 43.5) at 5 ° C. in a solution of 1- (4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (30.0 g, 146 mmol) and MOMCl (29.1 g, 364 mmol) in CS ₂ (300 mL) mmol) was added. The reaction mixture was heated at 30 ° C. for 1 day and poured into ice water. The mixture was extracted with CH ₂ Cl ₂ (150 mL × 3). The combined organic extracts were evaporated in vacuo to afford crude 1- (3-chloromethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (38.0 g) which was used in the next step without further purification.

Step c: 1- (3-hydroxymethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester

Bu ₄ NBr (4.0 g) and Na ₂ CO ₃ (90.0) at room temperature in a suspension of crude 1- (3-chloromethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (20.0 g) in water (350 mL) g, 0.85 mol) was added. The reaction mixture was heated at 65 ° C. overnight. The resulting solution was acidified with aqueous HCl (2 mol / L) and extracted with EtOAc (200 mL × 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford the crude product which was purified by column (petroleum ether / EtOAc 15: 1) to give 1- (3-hydroxymethyl- 4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (8.0 g, 39%) was obtained. ¹ H NMR (CDCl _3, 400 MHz) δ 7.23-7.26 (m, 2H), 6.83 (d, J = 8.0 Hz, 1H), 4.67 (s, 2H), 3.86 (s, 3H), 3.62 (s, 3H), 1.58 (q, J = 3.6 Hz, 2H), 1.14-1.17 (m, 2H).

Step d: 1- [3- ( tertiary butyl-dimethyl-silanyloxymethyl) -4-methoxy-phenyl] cyclopropane-carboxylic acid methyl ester

In a solution of 1- (3-hydroxymethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (8.0 g, 34 mmol) in CH ₂ Cl ₂ (100 mL) at room temperature, imidazole (5.8 g, 85 mmol) and TBSCl (7.6 g, 51 mmol) were added. The mixture was stirred at room temperature overnight. The mixture was washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford the crude product which was purified by column (petroleum ether / EtOAc 30: 1) to give 1- [3- ( tert butyl- Dimethyl-silanyloxymethyl) -4-methoxy-phenyl] -cyclopropanecarboxylic acid methyl ester (6.7 g, 56%) was obtained. ¹ H NMR (CDCl _{3 ,} 400 MHz) δ 7.44-7.45 (m, 1H), 7.19 (dd, J = 2.0, 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 4.75 (s, 2H), 3.81 (s, 3H), 3.62 (s, 3H), 1.57-1.60 (m, 2H), 1.15- 1.18 (m, 2H), 0.96 (s, 9H) , 0.11 (s, 6H).

Step e: 1- (3-hydroxymethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid

To a solution of 1- [3- ( tertiary butyl-dimethyl-silanyloxymethyl) -4-methoxy-phenyl] -cyclopropanecarboxylic acid methyl ester (6.2 g, 18 mmol) in MeOH (75 mL) in water at 0 ° C. (10 mL) A solution of LiOH.H ₂ O (1.50 g, 35.7 mmol) was added. The reaction mixture was stirred at 40 ° C. overnight. Evaporate under vacuum to remove MeOH. AcOH (1 mol / L, 40 mL) and EtOAc (200 mL) were added. The organic layer was separated, washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford 1- (3-hydroxymethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid (5.3 g). It was.

F. 2- (3- fluoro- 4 -methoxyphenyl ) acetonitrile

To a suspension of t-BuOK (25.3 g, 0.207 mol) in THF (150 mL) was added a solution of TosMIC (20.3 g, 0.104 mol) in THF (50 mL) at -78 ° C. The mixture was stirred for 15 minutes, treated by dropwise addition of a solution of 3-fluoro-4-methoxy-benzaldehyde (8.00 g, 51.9 mmol) in THF (50 mL), and stirring continued at -78 ° C for 1.5 hours. It was. Methanol (50 mL) was added to the cooled reaction mixture. The mixture was heated to reflux for 30 minutes. The solvent of the reaction mixture was removed to afford the crude product, which was dissolved in water (200 mL). The aqueous phase was extracted with EtOAc (100 mL × 3). The combined organic layers were dried and evaporated under reduced pressure to afford the crude product which was purified by column chromatography (petroleum ether / EtOAc 10: 1) to give 2- (3-fluoro-4-methoxyphenyl) acetonitrile ( 5.0 g, 58%) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.02-7.05 (m, 2H), 6.94 (t, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.67 (s, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 152.3, 147.5, 123.7, 122.5, 117.7, 115.8, 113.8, 56.3, 22.6.

G. 2- (3 -chloro- 4 -methoxyphenyl ) acetonitrile

To a suspension of t-BuOK (4.8 g, 40 mmol) in THF (30 mL) was added a solution of TosMIC (3.9 g, 20 mmol) in THF (10 mL) at -78 ° C. The mixture was stirred for 10 minutes, treated dropwise with a solution of 3-chloro-4-methoxy-benzaldehyde (1.65 g, 10 mmol) in THF (10 mL) and stirring continued at -78 ° C for 1.5 hours. Methanol (10 mL) was added to the cooled reaction mixture. The mixture was heated to reflux for 30 minutes. The solvent of the reaction mixture was removed to afford the crude product, which was dissolved in water (20 mL). The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic layers were dried and evaporated under reduced pressure to afford the crude product which was purified by column chromatography (petroleum ether / EtOAc 10: 1) to give 2- (3-chloro-4-methoxyphenyl) acetonitrile (1.5 g, 83%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33 (d, J = 2.4 Hz, 1 H), 7.20 (dd, J = 2.4, 8.4 Hz, 1 H), 6.92 (d, J = 8.4 Hz, 1 H ), 3.91 (s, 3H), 3.68 (s, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 154.8, 129.8, 127.3, 123.0, 122.7, 117.60, 112.4, 56.2, 22.4.

H. 1- (3,3-dimethyl-2,3 -dihydrobenzofuran -5-yl) cyclopropanecarboxylic acid

Step a: 1- (4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester

To a solution of methyl 1- (4-methoxyphenyl) cyclopropanecarboxylate (10.0 g, 48.5 mmol) in DCM (80 mL) was added EtSH (16 mL) under an ice water bath. The mixture was stirred at 0 ° C. for 20 minutes, then AlCl ₃ (19.5 g, 0.15 mmol) was added slowly at 0 ° C. The mixture was stirred at 0 < 0 > C for 30 minutes. The reaction mixture was poured into ice water, the organic layer was separated and the aqueous phase was extracted with DCM (50 mL × 3). The combined organic layers were washed with H ₂ O, brine, dried over Na ₂ SO ₄ and evaporated in vacuo to give 1- (4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester (8.9 g, 95%). It was. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.20-7.17 (m, 2H), 6.75-6.72 (m, 2H), 5.56 (s, 1H), 3.63 (s, 3H), 1.60-1.57 (m, 2H), 1.17-1.15 (m, 2H).

Step b: 1- (4-hydroxy-3,5-diiodo-phenyl) -cyclopropanecarboxylic acid methyl ester

NIS (15.6 g, 69 mmol) was added to a solution of 1- (4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester (8.9 g, 46 mmol) in CH ₃ CN (80 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether / EtOAc 10: 1) to give 1- (4-hydroxy-3,5-diiodo-phenyl) -cyclopropanecarboxylic acid methyl ester ( 3.5 g, 18%) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (s, 2 H), 5.71 (s, 1 H), 3.63 (s, 3 H), 1.59-1.56 (m, 2 H), 1.15-1.12 (m , 2 H).

Step c: 1- [3,5-Diiodo-4- (2-methyl-allyloxy) -phenyl] -cyclopropanecarboxylic acid methyl ester

1- (4-hydroxy-3,5-diiodo-phenyl) -cyclopropanecarboxylic acid methyl ester (3.2 g, 7.2 mmol) in acetone (20 mL), 3-chloro-2-methyl-propene (1.0 g, 11 mmol), K ₂ CO ₃ (1.2 g, 8.6 mmol), NaI (0.1 g, 0.7 mmol) was stirred at 20 ° C. overnight. The solid was filtered off and the filtrate was concentrated in vacuo to give 1- [3,5-diiodo-4- (2-methyl-allyloxy) -phenyl] -cyclopropane-carboxylic acid methyl ester (3.5 g, 97%). Obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.75 (s, 2 H), 5.26 (s, 1 H), 5.06 (s, 1 H), 4.38 (s, 2 H), 3.65 (s, 3 H) , 1.98 (s, 3H), 1.62-1.58 (m, 2H), 1.18-1.15 (m, 2H).

Step d: 1- (3,3-Dimethyl-2,3-dihydro-benzofuran-5-yl) -cyclopropanecarboxylic acid methyl ester

Bu ₃ SnH in a solution of 1- [3,5-diiodo-4- (2-methyl-allyloxy) -phenyl] -cyclopropane-carboxylic acid methyl ester (3.5 g, 7.0 mmol) in toluene (15 mL) (2.4 g, 8.4 mmol) and AIBN (0.1 g, 0.7 mmol) were added. The mixture was heated to reflux overnight. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether / EtOAc 20: 1) to give 1- (3,3-dimethyl-2,3-dihydro-benzofuran-5-yl). Cyclopropanecarboxylic acid methyl ester (1.05 g, 62%) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.10-7.07 (m, 2H), 6.71 (d, J = 8 Hz, 1H), 4.23 (s, 2H), 3.62 (s, 3H), 1.58-1.54 (m, 2H), 1.34 (s, 6H), 1.17-1.12 (m, 2H).

Step e: 1- (3,3-dimethyl-2,3-dihydrobenzofuran-5-yl) cyclopropanecarboxylic acid

LiOH (0.40 g, 9.5 mmol) in a solution of 1- (3,3-dimethyl-2,3-dihydro-benzofuran-5-yl) -cyclopropanecarboxylic acid methyl ester (1 g, 4 mmol) in MeOH (10 mL) ) Was added. The mixture was stirred at 40 ° C. overnight. HCl (10%) was added slowly to adjust the pH to 5. The resulting mixture was extracted with ethyl acetate (10 mL × 3). The extract was washed with brine and dried over Na ₂ S0 ₄ . The solvent was removed in vacuo and the crude product was purified by preparative HPLC to give 1- (3,3-dimethyl-2,3-dihydrobenzofuran-5-yl) cyclopropanecarboxylic acid (0.37 g, 41%). . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.11-7.07 (m, 2H), 6.71 (d, J = 8 Hz, 1H), 4.23 (s, 2H), 1.66-1.63 (m, 2H ), 1.32 (s, 6H), 1.26-1.23 (m, 2H).

I. 2- (7 -methoxybenzo [d] [1,3] dioxol -5-yl) acetonitrile

Step a: 3,4-dihydroxy-5-methoxybenzoate

In a solution of 3,4,5-trihydroxy-benzoic acid methyl ester (50 g, 0.27 mol) and Na ₂ B ₄ O ₇ (50 g) in water (1000 mL), a solution of Me ₂ SO ₄ (120 mL) and an aqueous NaOH solution ( 25%, 200 mL) was added continuously at room temperature. The mixture was stirred at rt for 6 h and then cooled to 0 ° C. The mixture was acidified to pH ˜2 by addition of concentrated H ₂ SO ₄ and then filtered. The filtrate was extracted with EtOAc (500 mL × 3). The combined organic phases were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to afford methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g 47%), which was next purified without further purification. Used in

Step b: Methyl 7-methoxybenzo [d] [1,3] dioxol-5-carboxylate

To a solution of methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g, 0.078 mol) in acetone (500 mL) at 80 ° C. CH ₂ BrCl (34.4 g, 0.27 mol) and K ₂ CO ₃ ( 75 g, 0.54 mol) was added. The resulting mixture was heated to reflux for 4 hours. The mixture was cooled to room temperature and the solid K ₂ CO ₃ was filtered off. The filtrate was concentrated under reduced pressure and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with water, dried over anhydrous Na ₂ S0 ₄ and evaporated under reduced pressure to afford the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10: 1) to give methyl 7-meth Toxoxybenzo [d] [1,3] dioxol-5-carboxylate (12.6 g, 80%) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32 (s, 1 H), 7.21 (s, 1 H), 6.05 (s, 2 H), 3.93 (s, 3 H), 3.88 (s, 3 H).

Step c: (7-methoxybenzo [d] [1,3] dioxol-5-yl) methanol

To a solution of methyl 7-methoxybenzo [d] [1,3] dioxol-5-carboxylate (13.9 g, 0.040 mol) in THF (100 mL) was diluted LiAlH ₄ (3.1 g, 0.080 mol) at room temperature. Was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0 ° C. and treated successively with water (3.1 g) and NaOH (10%, 3.1 mL). The slurry was filtered and washed with THF. The combined filtrates were evaporated under reduced pressure to give (7-methoxy-benzo [d] [1,3] dioxol-5-yl) methanol (7.2 g, 52%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.55 (s, 1H), 6.54 (s, 1H), 5.96 (s, 2H), 4.57 (s, 2H), 3.90 (s, 3H).

Step d: 6- (chloromethyl) -4-methoxybenzo [d] [1,3] dioxole

(7-methoxybenzo [d] [1,3] dioxol-5-yl) methanol (9.0 g, 54 mmol) was added to the solution of SOCl ₂ (150 mL) at 0 ° C. The mixture was stirred for 0.5 h. Excess SoCl ₂ was evaporated under reduced pressure to give the crude product, which was basified to pH ˜7 with saturated aqueous NaHCO ₃ . The aqueous phase was extracted with EtOAc (100 mL × 3). The combined organic phases were dried over anhydrous Na ₂ SO ₄ and evaporated to give 6- (chloromethyl) -4-methoxybenzo [d] [1,3] dioxol (10.2 g 94%), which was further Used in the next step without purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.58 (s, 1 H), 6.57 (s, 1 H), 5.98 (s, 2 H), 4.51 (s, 2 H), 3.90 (s, 3 H) .

Step e: 2- (7-methoxybenzo [d] [1,3] dioxol-5-yl) acetonitrile

6- (chloromethyl) -4-methoxybenzo [d] [1,3] dioxol in DMSO (100 mL) (10.2 g, 40 mmol) was added NaCN (2.43 g, 50 mmol) at room temperature. The mixture was stirred for 3 hours and poured into water (500 mL). The aqueous phase was extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated to afford the crude product, which was washed with ether to give 2- (7-methoxybenzo [d] [1,3] dioxol-5-yl) aceto Nitrile (4.6 g, 45%) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.49 (s, 2 H), 5.98 (s, 2 H), 3.91 (s, 3 H), 3.65 (s, 2 H). ¹³ C NMR (400 MHz, CDCl ₃ ) δ 148.9, 143.4, 134.6, 123.4, 117.3, 107.2, 101.8, 101.3, 56.3, 23.1.

J. 1- ( Benzofuran -5-yl) cyclopropanecarboxylic acid

Step a: 1- [4- (2,2-diethoxy-ethoxy) -phenyl] -cyclopropanecarboxylic acid

To a stirred solution of 1- (4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester (15.0 g, 84.3 mmol) in DMF (50 mL) sodium hydride (6.7 g, 170 mmol, 60% in mineral oil) at 0 ° C. Was added. After the hydrogen evolution ceased, 2-bromo-1,1-diethoxy-ethane (16.5 g, 84.3 mmol) was added dropwise to the reaction mixture. The reaction was stirred at 160 ° C. for 15 hours. The reaction mixture was poured into ice (100 g) and extracted with CH ₂ Cl ₂ . The combined organics were dried over Na ₂ SO ₄ . The solvent was removed in vacuo to afford crude 1- [4- (2,2-diethoxy-ethoxy) -phenyl] -cyclopropanecarboxylic acid (10 g) which was used directly in the next step without further purification.

Step b: 1-benzofuran-5-yl-cyclopropanecarboxylic acid

To a suspension of crude 1- [4- (2,2-diethoxy-ethoxy) -phenyl] -cyclopropanecarboxylic acid (20 g, ˜65 mmol) in xylene (100 mL) was added PPA (22.2 g, 64.9 mmol) at room temperature. Was added. The mixture was heated to reflux for 1 hour (140 ° C.), then cooled to room temperature and decanted from PPA. The solvent was evaporated in vacuo to afford the crude product which was purified by preparative HPLC to give 1- (benzofuran-5-yl) cyclopropanecarboxylic acid (1.5 g, 5%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.25 (br s, 1 H), 7.95 (d, J = 2.8 Hz, 1 H), 7.56 (d, J = 2.0 Hz, 1 H), 7.47 ( d, J = 11.6 Hz, 1 H), 7.25 (dd, J = 2.4, 11.2 Hz, 1 H), 6.89 (d, J = 1.6 Hz, 1 H), 1.47-1.44 (m, 2H), 1.17 -1.14 (m, 2H).

K. 1- (2,3 - Dihydrobenzofuran - 5-yl) cyclopropanecarboxylic acid

To a solution of 1- (benzofuran-5-yl) cyclopropanecarboxylic acid (700 mg, 3.47 mmol) in MeOH (10 mL) was added PtO ₂ (140 mg, 20%) at room temperature. The stirred reaction mixture was hydrogenated at 10 ° C. under hydrogen (1 atm) for 3 days. The reaction mixture was filtered. The solvent was evaporated in vacuo to afford the crude product which was purified by preparative HPLC to give 1- (2,3-dihydrobenzofuran-5-yl) cyclopropanecarboxylic acid (330 mg, 47%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.20 (s, 1 H), 7.10 (d, J = 10.8 Hz, 1 H), 6.73 (d, J = 11.2 Hz, 1 H), 4.57 (t, J = 11.6 Hz, 2H), 3.20 (t, J = 11.6 Hz, 2H), 1.67-1.63 (m, 2H), 1.25-1.21 (m, 2H).

L. 2- (2,2- Dimethylbenzo [d] [1,3] dioxol -5-yl) acetonitrile

Step a: (3,4-dihydroxy-phenyl) -acetonitrile

To a solution of benzo [1,3] dioxol-5-yl-acetonitrile (0.50 g, 3.1 mmol) in CH ₂ Cl ₂ (15 mL) BBr ₃ (0.78 g, 3.1 mmol) under N ₂ at −78 ° C. Was added dropwise. The mixture was slowly warmed up to room temperature and stirred overnight. H ₂ O (10 mL) was added to stop the reaction and the CH ₂ Cl ₂ layer was separated. The aqueous phase was extracted with CH ₂ Cl ₂ (2 × 7 mL). The combined organics were washed with brine, dried over Na ₂ SO ₄ and purified by column chromatography on silica gel (petroleum ether / EtOAc 5: 1) to give (3,4-dihydroxy-phenyl) -acetonitrile as a white solid. (0.25 g, 54%) was obtained. ¹ H NMR (DMSO- d _{6 ,} 400 MHz) δ 9.07 (s, 1 H), 8.95 (s, 1 H), 6.68-6.70 (m, 2H), 6.55 (dd, J = 8.0, 2.0 Hz, 1 H), 3.32 (s, 2 H).

Step b: 2- (2,2-dimethylbenzo [d] [1,3] dioxol-5-yl) acetonitrile

To a solution of (3,4-dihydroxy-phenyl) -acetonitrile (0.2 g, 1.3 mmol) in toluene (4 mL) 2,2-dimethoxy-propane (0.28 g, 2.6 mmol) and TsOH (0.010 g) , 0.065 mmol) was added. The mixture was heated to reflux overnight. The reaction mixture was evaporated to remove the solvent and the residue was dissolved in ethyl acetate. The organic layer was washed with NaHCO ₃ solution, H ₂ O, brine and dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether / EtOAc 10: 1) to give 2- (2,2-dimethylbenzo [d] [1,3] dioxol-5 -Yl) acetonitrile (40 mg, 20%) was obtained. ¹ H NMR (CDCl ₃ , 400 MHz) δ 6.68-6.71 (m, 3H), 3.64 (s, 2H), 1.67 (s, 6H).

M. 2- (3- ( benzyloxy ) -4 -chlorophenyl ) acetonitrile

Step a: (4-chloro-3-hydroxy-phenyl) acetonitrile

BBr ₃ (16.6 g, 66 mmol) was added slowly to a solution of 2- (4-chloro-3-methoxyphenyl) acetonitrile (12 g, 66 mmol) in DCM (120 mL) at −78 ° C. under N ₂ . The reaction temperature was slowly raised to room temperature. The reaction mixture was stirred overnight and then poured into ice water. The organic layer was separated and the aqueous layer extracted with DCM (40 mL × 3). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give (4-chloro-3-hydroxy-phenyl) -acetonitrile (9.3 g, 85%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.34 (d, J = 8.4 Hz, 1 H), 7.02 (d, J = 2.1 Hz, 1 H), 6.87 (dd, J = 2.1, 8.4 Hz, 1 H ), 5.15 (brs, 1 H), 3.72 (s, 2 H).

Step b: 2- (3- (benzyloxy) -4-chlorophenyl) acetonitrile

To a solution of (4-chloro-3-hydroxy-phenyl) acetonitrile (6.2 g, 37 mmol) in CH ₃ CN (80 mL) was charged K ₂ CO ₃ (10.2 g, 74 mmol) and BnBr (7.6 g, 44 mmol). Was added. The mixture was stirred at room temperature overnight. The solid was filtered off and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 50: 1) to give 2- (3- (benzyloxy) -4-chlorophenyl) acetonitrile (5.6 g, 60%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48-7.32 (m, 6H), 6.94 (d, J = 2 Hz, 2H), 6.86 (dd, J = 2.0, 8.4 Hz, 1H), 5.18 (s, 2H), 3.71 (s, 2H).

N. 2- ( Quinoxaline Yl) Acetonitrile

Step a: 6-methylquinoxaline

To a solution of 4-methylbenzene-1,2-diamine (50.0 g, 0.41 mol) in isopropanol (300 mL) was added a solution of glyoxal (40% in water, 65.3 g, 0.45 mol) at room temperature. The reaction mixture was heated at 80 ° C. for 2 hours and then evaporated in vacuo to give 6-methylquinoxaline (55 g, 93%), which was used directly in the next step. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.77 (dd, J = 1.5, 7.2 Hz, 2 H), 7.99 (d, J = 8.7 Hz, 1 H), 7.87 (s, 1 H), 7.60 (dd , J = 1.5, 8.4 Hz, 1 H), 2.59 (s, 3 H).

Step b: 6-bromomethylquinoxaline

To a solution of 6-methylquinoxaline (10.0 g, 69.4 mmol) in CCl ₄ (80 mL) was added NBS (13.5 g, 76.3 mmol) and benzoyl peroxide (BP, 1.7 g, 6.9 mmol) at room temperature. The mixture was heated to reflux for 2 hours. After cooling, the mixture was evaporated in vacuo to give a yellow solid which was extracted with petroleum ether (50 mL × 5). The extract was concentrated in vacuo. The organics were combined and concentrated to give crude 6-bromomethylquinoxaline (12.0 g), which was used directly in the next step. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.85-8.87 (m, 2H), 8.10-8.13 (m, 2H), 7.82 (dd, J = 2.1, 8.7 Hz, 1H), 4.70 (s, 2 H).

Step c: 2- (quinoxalin-6-yl) acetonitrile

To a solution of crude 6-bromomethylquinoxaline (36.0 g) in 95% ethanol (200 mL) was added NaCN (30.9 g, 0.63 mol) at room temperature. The mixture was heated at 50 ° C. for 3 h and then concentrated in vacuo. Water (100 mL) and ethyl acetate (100 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether / EtOAc 10: 1) to give 2- (quinoxalin-6-yl) acetonitrile (7.9 g, 23% for two steps). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.88-8.90 (m, 2H), 8.12-8.18 (m, 2H), 7.74 (dd, J = 2.1, 8.7 Hz, 1H), 4.02 (s, 2 H). MS (ESI) m / z (M + H) ⁺ 170.0.

O. 2- (quinolin-6-yl) acetonitrile

Step a: 6-bromomethylquinoline

To a solution of 6-methylquinoline (2.15 g, 15.0 mmol) in CCl ₄ (30 mL) was added NBS (2.92 g, 16.5 mmol) and benzoyl peroxide (BP, 0.36 g, 1.5 mmol) at room temperature. The mixture was heated to reflux for 2 hours. After cooling, the mixture was evaporated in vacuo to give a yellow solid which was extracted with petroleum ether (30 mL × 5). The extract was concentrated in vacuo to afford crude 6-bromomethylquinoline (1.8 g), which was used directly in the next step.

Step b: 2- (quinolin-6-yl) acetonitrile

To a solution of crude 6-bromomethylquinoline (1.8 g) in 95% ethanol (30 mL) was added NaCN (2.0 g, 40.8 mmol) at room temperature. The mixture was heated at 50 ° C. for 3 h and then concentrated in vacuo. Water (50 mL) and ethyl acetate (50 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. The combined crude product was purified by column (petroleum ether / EtOAc 5: 1) to give 2- (quinolin-6-yl) acetonitrile (0.25 g, 8% for two steps). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.95 (dd, J = 1.5, 4.2 Hz, 1 H), 8.12-8.19 (m, 2H), 7.85 (s, 1H), 7.62 (dd, J = 2.1, 8.7 Hz, 1 H), 7.46 (q, J = 4.2 Hz, 1 H), 3.96 (s, 2 H). MS (ESI) m / e (M + H) ⁺ 169.0.

P. 2- (2,3 -dihydrobenzo [b] [1,4] dioxin -6-yl) acetonitrile

Step a: 2,3-dihydro-benzo [1,4] dioxin-6-carboxylic acid ethyl ester

In a suspension of Cs ₂ CO ₃ (270 g, 1.49 mol) in DMF (1000 mL), 3,4-dihydroxybenzoic acid ethyl ester (54.6 g, 0.3 mol) and 1,2-dibromoethane (54.3 g) at room temperature , 0.29 mol) was added. The resulting mixture was stirred at 80 ° C. overnight and then poured into ice water. The mixture was extracted with EtOAc (200 mL × 3). The combined organic layers were washed with water (200 mL × 3) and brine (100 mL), dried over Na ₂ SO ₄ , and concentrated to dryness. The residue was purified by column (petroleum ether / ethyl acetate 50: 1) on silica gel to give 2,3-dihydro-benzo [1,4] dioxin-6-carboxylic acid ethyl ester (18 g, 29%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.53 (dd, J = 1.8, 7.2 Hz, 2H), 6.84-6.87 (m, 1H), 4.22-4.34 (m, 6H), 1.35 (t, J = 7.2 Hz, 3 H).

Step b: (2,3-Dihydro-benzo [1,4] dioxin-6-yl) -methanol

To a suspension of LAH (2.8 g, 74 mmol) in THF (20 mL) 2,3-dihydro-benzo [1,4] dioxin-6-carboxylic acid ethyl ester in THF (10 mL) at 0 ° C. under N ₂ at 15 ° C. , 72 mmol) was added dropwise. The mixture was stirred at rt for 1 h and then quenched carefully by addition of water (2.8 mL) and NaOH (10%, 28 mL) while cooling. The precipitated solid was filtered off and the filtrate was evaporated to dryness to afford (2,3-dihydro-benzo [1,4] dioxin-6-yl) -methanol (10.6 g). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.73-6.78 (m, 3H), 5.02 (t, J = 5.7 Hz, 1H), 4.34 (d, J = 6.0 Hz, 2H), 4.17 -4.20 (m, 4H).

Step c: 6-chloromethyl-2,3-dihydro-benzo [1,4] dioxine

A mixture of (2,3-dihydro-benzo [1,4] dioxin-6-yl) methanol (10.6 g) in SOCl ₂ (10 mL) was stirred at room temperature for 10 minutes and then poured into ice water. The organic layer was separated and the aqueous phase extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with NaHCO ₃ (saturated solution), water and brine, dried over Na ₂ SO ₄ and concentrated to dryness to give 6-chloromethyl-2,3-dihydro-benzo [1,4] di. Auxin (12 g, 88% for two steps) was obtained and used directly in the next step.

Step d: 2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) acetonitrile

A mixture of 6-chloromethyl-2,3-dihydro-benzo [1,4] dioxine (12.5 g, 67.7 mmol) and NaCN (4.30 g, 87.8 mmol) in DMSO (50 mL) was stirred at room temperature for 1 hour. Stirred. The mixture was poured into water (150 mL) and then extracted with dichloromethane (50 mL × 4). The combined organic layers were washed with water (50 mL × 2) and brine (50 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by column (petroleum ether / ethyl acetate 50: 1) on silica gel to give 2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) acetonitrile as a yellow oil ( 10.2 g, 86%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.78-6.86 (m, 3 H), 4.25 (s, 4 H), 3.63 (s, 2 H).

Q. 2- (2,2,4,4 -tetrafluoro- 4H- benzo [d] [1,3] dioxin -6-yl) acetonitrile

Step a: 2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxin-6-carboxylic acid methyl ester

6-Bromo-2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxine (4.75 g) in MeOH (20 mL), MeCN (30 mL) and Et ₃ N (10 mL) , 16.6 mmol) and Pd (PPh ₃ ) ₄ (950 mg, 8.23 mmol) were stirred overnight at 75 ° C. (oil bath temperature) under a carbon monoxide atmosphere (55 psi). The cooled reaction mixture was filtered and the filtrate was concentrated. The residue was purified by a silica gel column (petroleum ether) to give 2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxin-6-carboxylic acid methyl ester (3.75 g, 85%). Obtained. ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.34 (s, 1 H), 8.26 (dd, J = 2.1, 8.7 Hz, 1 H), 7.22 (d, J = 8.7 Hz, 1 H), 3.96 (s , 3 H).

Step b: (2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxin-6-yl) methanol

To a suspension of LAH (2.14 g, 56.4 mmol) in dry THF (200 mL), 2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxine in dry THF (50 mL) at 0 ° C. A solution of -6-carboxylic acid methyl ester (7.50 g, 28.2 mmol) was added dropwise. After stirring for 1 h at 0 ° C., the reaction mixture was treated with water (2.14 g) and 10% NaOH (2.14 mL). The slurry was filtered and washed with THF. The combined filtrates were evaporated to dryness to afford crude (2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxin-6-yl) -methanol (6.5 g), which was taken to the next step. Used directly at ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.64 (s, 1 H), 7.57-7.60 (m, 1 H), 7.58 (d, J = 8.7 Hz, 1 H), 4.75 (s, 2 H).

Step c: 6-chloromethyl-2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxine

A mixture of (2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxin-6-yl) -methanol (6.5 g) in thionyl chloride (75 mL) was heated to reflux overnight. The resulting mixture was concentrated in vacuo. The residue was basified with aqueous saturated NaHCO ₃ . The aqueous layer was extracted with dichloromethane (50 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 6-chloromethyl-2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxin (6.2 g). Was obtained and used directly in the next step. ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.65 (s, 1 H), 7.61 (dd, J = 2.1, 8.7 Hz, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 4.60 (s , 2 H).

Step d: (2,2,4,4-Tetrafluoro-4H-benzo [1,3] dioxin-6-yl) -acetonitrile

A mixture of 6-chloromethyl-2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxine (6.2 g) and NaCN (2.07 g, 42.3 mmol) in DMSO (50 mL) was cooled to room temperature. Stirred for 2 h. The reaction mixture was poured into ice and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated to sour the crude product, which was purified by silica gel column (petroleum ether / EtOAc 10: 1) to give (2,2-difluoro-benzo [1, 3] dioxol-5-yl) -acetonitrile (4.5 g, 68% for three steps) was obtained. ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.57-7.60 (m, 2H), 7.20 (d, J = 8.7 Hz, 1H), 3.82 (s, 2H).

R. 2- (4H- Benzo [d] [1,3] dioxin -7-yl) acetonitrile

Step a: (3-hydroxyphenyl) acetonitrile

To a solution of (3-methoxyphenyl) acetonitrile (150 g, 1.03 mol) in CH ₂ Cl ₂ (1000 mL) was added dropwise BBr ₃ (774 g, 3.09 mol) at −70 ° C. The mixture was stirred and warmed to room temperature. Water (300 mL) was added at 0 ° C. The resulting mixture was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo. The crude residue was purified by column (petroleum ether / EtOAc 10: 1) to give (3-hydroxyphenyl) acetonitrile (75.0 g, 55%). ¹ H NMR (CDCl _{3 ,} 300 MHz) δ 7.18-7.24 (m, 1 H), 6.79-6.84 (m, 3 H), 3.69 (s, 2 H).

Step b: 2- (4H-Benzo [d] [1,3] dioxin-7-yl) acetonitrile

To a solution of (3-hydroxyphenyl) acetonitrile (75.0 g, 0.56 mol) in toluene (750 mL) at room temperature, paraformaldehyde (84.0 g, 2.80 mol) and toluene-4-sulfonic acid monohydrate (10.7 g, 56.0 mmol) was added. The reaction mixture was heated to reflux for 40 minutes. Toluene was removed by evaporation. Water (150 mL) and ethyl acetate (150 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo. The residue was separated by preparative HPLC to give 2- (4H-benzo [d] [1,3] dioxin-7-yl) acetonitrile (4.7 g, 5%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.85-6.98 (m, 3H), 5.25 (d, J = 3.0 Hz, 2H), 4.89 (s, 2H), 3.69 (s, 2H).

S. 2- (4H- Benzo [d] [1,3] dioxin -6-yl) acetonitrile

To a solution of (4-hydroxyphenyl) acetonitrile (17.3 g, 0.13 mol) in toluene (350 mL) at room temperature, paraformaldehyde (39.0 g, 0.43 mmol) and toluene-4-sulfonic acid monohydrate (2.5 g, 13 mmol) was added. The reaction mixture was heated to reflux for 1 hour. Toluene was removed by evaporation. Water (150 mL) and ethyl acetate (150 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was separated by preparative HPLC to give 2- (4H-benzo [d] [1,3] dioxin-6-yl) acetonitrile (7.35 g, 32%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.07-7.11 (m, 1 H), 6.95-6.95 (m, 1 H), 6.88 (d, J = 11.6 Hz, 1 H), 5.24 (s, 2 H ), 4.89 (s, 2H), 3.67 (s, 2H).

T. 2- (3- ( benzyloxy ) -4 -methoxyphenyl ) acetonitrile

To a suspension of t-BuOK (20.15 g, 0.165 mol) in THF (250 mL) was added a solution of TosMIC (16.1 g, 82.6 mmol) in THF (100 mL) at -78 ° C. The mixture was stirred for 15 minutes, treated dropwise with a solution of 3-benzyloxy-4-methoxy-benzaldehyde (10.0 g, 51.9 mmol) in THF (50 mL) and stirring continued at -78 ° C for 1.5 hours. . Methanol (50 mL) was added to the cooled reaction mixture. The mixture was heated to reflux for 30 minutes. The solvent of the reaction mixture was removed to afford the crude product, which was dissolved in water (300 mL). The aqueous phase was extracted with EtOAc (100 mL × 3). The combined organic layers were dried and evaporated under reduced pressure to afford the crude product which was purified by column chromatography (petroleum ether / EtOAc 10: 1) to give 2- (3- (benzyloxy) -4-methoxyphenyl) aceto Nitrile (5.0 g, 48%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.48-7.33 (m, 5 H), 6.89-6.86 (m, 3 H), 5.17 (s, 2 H), 3.90 (s, 3 H), 3.66 (s, 2 H). ¹³ C NMR (75 MHz, CDCl ₃ ) δ 149.6, 148.6, 136.8, 128.8, 128.8, 128.2, 127.5, 127.5, 122.1, 120.9, 118.2, 113.8, 112.2, 71.2, 56.2, 23.3.

Table 2 below contains a list of carboxylic acid building blocks, either commercially available or made by one of the methods described above.

U. 6 -Chloro- 5 -methylpyridin - 2 -amine

Step a: 2,2-Dimethyl- N- (5-methyl-pyridin-2-yl) -propionamide

To a stirred solution of 5-methylpyridin-2-amine (200 g, 1.85 mol) in anhydrous CH ₂ Cl ₂ (1000 mL), Et ₃ N (513 mL, 3.70 mol) and 2,2-dimethyl under N ₂ at 0 ° C. A solution of propionyl chloride (274 mL, 2.22 mol) was added dropwise. The ice bath was removed and stirring continued for 2 hours at room temperature. The reaction was poured into ice (2000 g). The organic layer was separated and the remaining aqueous layer was extracted with CH ₂ Cl ₂ (3 ×). The combined organics were dried over Na ₂ SO ₄ and evaporated to afford 2,2-dimethyl- N- (5-methyl-pyridin-2-yl) -propionamide (350 g), which was taken without further purification to the next step Used in ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12 (d, J = 8.4 Hz, 1 H), 8.06 (d, J = 1.2 Hz, 1 H), 7.96 (s, 1 H), 7.49 (dd, J = 1.6, 8.4 Hz, 1 H), 2.27 (s, 1 H), 1.30 (s, 9 H).

Step b: 2,2-Dimethyl- N- (5-methyl-1-oxy-pyridin-2-yl) -propionamide

To a stirred solution of 2,2-dimethyl- N- (5-methyl-pyridin-2-yl) -propionamide (100 g, 0.52 mol) in AcOH (500 mL) at room temperature 30% H ₂ O ₂ (80 mL, 2.6 mol) was added dropwise. The mixture was stirred at 80 ° C for 12 h. The reaction mixture was evaporated in vacuo to afford 2,2-dimethyl- N- (5-methyl-1-oxy-pyridin-2-yl) -propionamide (80 g, purity 85%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.26 (br s, 1 H), 8.33 (d, J = 8.4 Hz, 1 H), 8.12 (s, 1 H), 7.17 (dd, J = 0.8, 8.8 Hz, 1 H), 2.28 (s, 1 H), 1.34 (s, 9 H).

Step c: N- (6-Chloro-5-methyl-pyridin-2-yl) -2,2-dimethyl-propionamide

Et ₃ N at room temperature in a stirred solution of 2,2-dimethyl- N- (5-methyl-1-oxy-pyridin-2-yl) -propionamide (10 g, 48 mmol) in anhydrous CH ₂ Cl ₂ (50 mL). (60 mL, 240 mmol) was added. After stirring for 30 minutes, POCl ₃ (20 mL) was added dropwise to the reaction mixture. The reaction was stirred at 50 ° C. for 15 hours. The reaction mixture was poured into ice (200 g). The organic layer was separated and the remaining aqueous layer was extracted with CH ₂ Cl ₂ (3 ×). The combined organics were dried over Na ₂ SO ₄ . The solvent was evaporated in vacuo to afford the crude product which was purified by chromatography (petroleum ether / EtOAc 100: 1) to give N- (6-chloro-5-methyl-pyridin-2-yl) -2,2-dimethyl -Propionamide (0.5 g, 5%) was provided. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (d, J = 8.0 Hz, 1 H), 7.94 (br s, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 2.33 (s, 1 H), 1.30 (s, 9 H).

Step d: 6-Chloro-5-methyl-pyridin-2-ylamine

To N- (6-chloro-5-methyl-pyridin-2-yl) -2,2-dimethyl-propionamide (4.00 g, 17.7 mmol) was added 6N HCl (20 mL) at room temperature. The mixture was stirred at 80 ° C for 12 h. The reaction mixture was basified to pH 8-9 with the dropwise addition of saturated NaHCO ₃ , then the mixture was extracted with CH ₂ Cl ₂ (3 ×). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo to give 6-chloro-5-methyl-pyridin-2-ylamine (900 mg, 36%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.28 (d, J = 8.0 Hz, 1 H), 6.35 (d, J = 8.0 Hz, 1 H), 4.39 (br s, 2 H), 2.22 (s, 3 H). MS (ESI) m / z: 143 (M + H ⁺ ).

V. 6 -Chloro- 5 ( trifluoromethyl ) pyridin-2-amine

2,6-Dichloro-3- (trifluoromethyl) pyridine (5.00 g, 23.2 mmol) and 28% aqueous ammonia (150 mL) were placed in a 250 mL autoclave. The mixture was heated at 93 ° C for 21 h. The reaction was cooled to rt and extracted with EtOAc (100 mL × 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to afford the crude product, which was purified by column chromatography on silica gel (2-20% EtOAc in petroleum ether as eluent) to 6-chloro-5 -(Trifluoromethyl) pyridin-2-amine (2.1 g, 46% yield) was obtained. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.69 (d, J = 8.4 Hz, 1 H), 7.13 (br s, 2 H), 6.43 (d, J = 8.4 Hz, 1 H). MS (ESI) m / z (M + H) ⁺ 197.2

General Process IV: Coupling Reaction

One equivalent of a suitable carboxylic acid was placed in an oven dried flask under nitrogen. Thionyl chloride (3 equiv) and catalytic amount of N, N -dimethylformamide were added and the solution was stirred at 60 ° C. for 30 minutes. Excess thionyl chloride was removed under vacuum and the obtained solid was suspended in a minimum amount of anhydrous pyridine. The solution was added to 1 equivalent of an appropriate aminoheterocycle stirred solution dissolved in a minimum amount of anhydrous pyridine. The resulting mixture was stirred at 110 ° C. for 15 hours. The mixture was evaporated to dryness, suspended in dichloromethane and then extracted three times with 1N NaOH. The organic layer was then dried over sodium sulfate, evaporated to dryness and then purified by column chromatography.

W. 1- (benzo [d] [1,3] dioxol-5-yl) - N - (5- bromo-2-yl) cyclopropane-carboxamide (B-1)

1-Benzo [1,3] dioxol-5-yl-cyclopropanecarboxylic acid (2.38 g, 11.5 mmol) was placed in an oven dried flask under nitrogen. Thionyl chloride (2.5 mL) and N, N -dimethylformamide (0.3 mL) were added and the solution was stirred at 60 ° C. for 30 minutes. Excess thionyl chloride was removed under vacuum and the obtained solid was suspended in 7 ml of anhydrous pyridine. The solution was then slowly added to a solution of 5-bromo-pyridin-2-ylamine (2.00 g, 11.6 mmol) suspended in 10 ml of anhydrous pyridine. The resulting mixture was stirred at 110 ° C. for 15 hours. The mixture was then evaporated to dryness, suspended in 100 ml of dichloromethane and washed with three portions of 25 ml of 1N NaOH. The organic layer was dried over sodium sulfate, evaporated to near dryness, and then purified by silica gel column chromatography using dichloromethane as eluent to afford the pure product (3.46 g, 83%). ESI-MS m / z calc. 361.2, found 362.1 (M + 1) ⁺ ; Retention time 3.40 minutes. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.06-1.21 (m, 2H), 1.44-1.51 (m, 2H), 6.07 (s, 2H), 6.93-7.02 (m, 2H), 7.10 (d , J = 1.6 Hz, 1H), 8.02 (d, J = 1.6 Hz, 2H), 8.34 (s, 1H), 8.45 (s, 1H).

X. 1- (benzo [d] [1,3] dioxol-6-yl) - N - (6- bromopyridin-2-yl) cyclopropane-carboxamide (B-2)

(1-Benzo [1,3] dioxol-5-yl-cyclopropanecarboxylic acid (1.2 g, 5.8 mmol) was placed in an oven dried flask under nitrogen Thionyl chloride (2.5 mL) and N, N -dimethylform Amide (0.3 mL) was added and the solution was stirred for 30 min at 60 ° C. Excess thionyl chloride was removed in vacuo and the obtained solid was suspended in 5 mL of anhydrous pyridine. To the solution of 6-bromopyridin-2-amine (1.0 g, 5.8 mmol) suspended in ml was added slowly The resulting mixture was stirred for 15 h at 110 ° C. The mixture was then evaporated to dryness, Suspended in 50 ml of dichloromethane and washed with three portions of 20 ml of 1N NaOH The organic layer was dried over sodium sulfate, evaporated to near dryness, and then dichloromethane containing 2.5% triethylamine as eluent. Silica gel column chromatography Purification by chromatography yielded the pure product ESI-MS m / z calc. 361.2, found 362.1 (M + 1) ⁺ ; retention time 3.43 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.10-1.17 ( m, 2H), 1.42-1.55 (m, 2H), 6.06 (s, 2H), 6.92-7.02 (m, 2H), 7.09 (d, J = 1.6 Hz, 1H), 7.33 (d, J = 7.6 Hz , 1H), 7.73 (t, J = 8.0 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 8.78 (s, 1H).

The compounds in the following Table 3 were prepared in a similar manner as described above:

General Process V: Compound of Formula (I)

A suitable aryl halide (1 equiv) was dissolved in 1 mL of N, N -dimethylformamide (DMF) in the reaction tube. Suitable boronic acid (1.3 equiv), 0.1 mL (2 equiv) of aqueous 2M potassium carbonate solution and catalytic amount of Pd (dppf) Cl ₂ (0.09 equiv) are added and the reaction mixture is added at 80 ° C. for 3 hours, or at 150 ° C. for 5 hours. Heat in microwave for minutes. The obtained material was cooled to room temperature, filtered and purified by reverse phase preparative liquid chromatography.

Y. 1- Benzo [1,3] dioxol -5-yl- cyclopropanecarboxylic acid [5- (2,4 -dimethoxy - phenyl ) -pyridin-2-yl] -amide

1-Benzo [1,3] dioxol-5-yl-cyclopropanecarboxylic acid (5-bromo-pyridin-2-yl) -amide (36.1 mg, 0.10 mmol) was added to N, N -dimethylformamide in the reaction tube. Dissolved in 1 ml. 2,4-dimethoxybenzeneboronic acid (24 mg, 0.13 mmol), 0.1 ml of 2M aqueous potassium carbonate solution and catalytic amount of Pd (dppf) Cl ₂ (6.6 mg, 0.0090 mmol) were added, and the reaction mixture was stirred at 80 DEG C for 3 hours. Heated. The obtained material was cooled to room temperature, filtered and purified by reverse phase preparative liquid chromatography to give the pure product as trifluoroacetic acid salt. ESI-MS m / z calc. 418.2. Found 419.0 (M + 1) ⁺ . Retention time 3.18 minutes. ¹ H NMR (400 MHz, CD ₃ CN) δ 1.25-1.29 (m, 2H), 1.63-1.67 (m, 2H), 3.83 (s, 3H), 3.86 (s, 3H), 6.04 (s, 2H) , 6.64-6.68 (m, 2H), 6.92 (d, J = 8.4 Hz, 1H), 7.03-7.06 (m, 2H), 7.30 (d, J = 8.3 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 8.14 (dd, J = 8.9, 2.3 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.65 (s, 1H).

Z. 1- Benzo [1,3] dioxol -5-yl- cyclopropanecarboxylic acid [6- (4-dimethylamino- phenyl ) -pyridin-2-yl] -amide

1-Benzo [1,3] dioxol-5-yl-cyclopropanecarboxylic acid (6-bromo-pyridin-2-yl) -amide (36 mg, 0.10 mmol) was added to the reaction tube with N, N -dimethylformamide. Dissolved in 1 ml. 4- (dimethylamino) phenylboronic acid (21 mg, 0.13 mmol), 0.1 ml of 2M aqueous potassium carbonate solution and (Pd (dppf) Cl ₂ (6.6 mg, 0.0090 mmol)) were added and the reaction mixture was stirred at 80 ° C. for 3 hours. The obtained material was cooled to room temperature, filtered and purified by reverse phase preparative liquid chromatography to give the pure product as trifluoroacetic acid salt: ESI-MS m / z calc. 401.2, found 402.5 (M + 1) ) ^+. retention time 2.96 ^{minutes. 1 H NMR (400 MHz,} CD 3 CN) δ 1.23-1.27 (m, 2H), 1.62-1.66 (m, 2H), 3.04 (s, 6H), 6.06 (s, 2H ), 6.88-6.90 (m, 2H), 6.93-6.96 (m, 1H), 7.05-7.07 (m, 2H), 7.53-7.56 (m, 1H), 7.77-7.81 (m, 3H), 7.84-7.89 (m, 1 H), 8.34 (s, 1 H).

The following reaction scheme was used to prepare additional boronic acid esters that are not commercially available.

AA. 1- Methyl -4- [4- (4,4,5,5- tetramethyl- 1,3,2 -dioxaborolan -2-yl) phenyl ] -sulfonylpiperazine

Step a: 1- (4-bromophenylsulfonyl) -4-methylpiperazine

A solution of 4-bromobenzene-1-sulfonyl chloride (256 mg, 1.00 mmol) in 1 mL of dichloromethane was added to 5 mL of a saturated aqueous solution of sodium bicarbonate, dichloromethane (5 mL) and 1-methylpiperazine (100 mg, 1.00 mmol) was added slowly to the vial (40 mL). The reaction was stirred overnight at room temperature. The phases were separated and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the required product which was used in the next step without further purification. ESI-MS m / z calc. 318.0, found 318.9 (M + 1) ⁺ . Retention time 1.30 minutes. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.65 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 3.03 (t, J = 4.2 Hz, 4H), 2.48 (t , J = 4.2 Hz, 4H), 2.26 (s, 3H).

Step b: 1-Methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] sulfonyl-piperazine

In a 50 ml round bottom flask, 1- (4-bromophenyl-sulfonyl) -4-methylpiperazine (110 mg, 0.350 mmol), bis- (pinacolato) in N, N -dimethylformamide (6 ml) -Diboron (93 mg, 0.37 mmol), palladium acetate (6 mg, 0.02 mmol) and potassium acetate (103 mg, 1.05 mmol) were charged. The mixture was degassed by lightly bubbling argon through the solution at room temperature for 30 minutes. The mixture was then heated at 80 ° C. under argon until the reaction was complete (4 h). Desired product, 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -sulfonyl-piperazine and vias Reel product, 4- (4-methylpiperazin-1-ylsulfonyl) -phenyl-phenylsulfonyl-4-methylpiperazine, was obtained in a ratio of 1: 2 as shown by LC / MS analysis. The mixture was used without further purification.

BB. 4,4,5,5- tetramethyl- 2- (4- (2- ( methylsulfonyl ) ethyl) phenyl ) -1,3,2 -dioxaborolane

Step a: 4-bromophenethyl-4-methylbenzenesulfonate

P -bromophenethyl alcohol (1.0 g, 4.9 mmol) was added to a 50 mL round bottom flask followed by pyridine (15 mL). To the clear solution, p -toluenesulfonyl chloride (TsCl) (1.4 g, 7.5 mmol) was added as a solid under argon. The reaction mixture was purged with argon and stirred at rt for 18 h. The crude mixture was treated with 1N HCl (20 mL) and extracted with ethyl acetate (5 × 25 mL). The organic fractions were dried over Na ₂ SO ₄ , filtered and concentrated to afford 4-bromophenethyl-4-methylbenzenesulfonate (0.60 g, 35%) as a yellow liquid. ¹ H-NMR (acetone- d ₆ , 300 MHz) δ 7.64 (d, J = 8.4 Hz, 2H), 7.40-7.37 (d, J = 8.7 Hz, 4H), 7.09 (d, J = 8.5 Hz, 2H ), 4.25 (t, J = 6.9 Hz, 2H), 2.92 (t, J = 6.3 Hz, 2H), 2.45 (s, 3H).

Step b: (4-bromophenethyl) (methyl) sulfan

To a 20 mL round bottom flask was added 4-bromophenethyl 4-methylbenzenesulfonate (0.354 g, 0.996 mmol) and CH ₃ SNa (0.10 g, 1.5 mmol), then THF (1.5 mL) and N -methyl-2- Pyrrolidinone (1.0 mL) was added. The mixture was stirred at rt for 48 h and then treated with a saturated aqueous solution of sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (4 × 10 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give (4-bromophenethyl) (methyl) sulfan (0.30 g, crude product) as a yellow oil. It was. ¹ H-NMR (CDCl ₃ , 300 MHz) δ 7.40 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 2.89-2.81 (m, 2H), 2.74-2.69 (m , 2H), 2.10 (s, 3H).

Step c: 1-bromo-4- (2-methylsulfonyl) -ethylbenzene

To a 20 mL round bottom flask was added (4-bromophenethyl)-(methyl) sulfan (0.311 g, 1.34 mmol) and oxone (3.1 g, 0.020 mol), and then a 1: 1 mixture of acetone / water (10 mL) was added. Was added. The mixture was vigorously stirred at rt for 20 h and then concentrated. The aqueous mixture was extracted with ethyl acetate (3 × 15 mL) and dichloromethane (3 × 10 mL). The organic fractions were combined, dried over Na ₂ S0 ₄ , filtered and concentrated to give a white semisolid. The crude material was purified by flash chromatography to yield 1-bromo-4- (2-methylsulfonyl) -ethylbenzene (0.283 g, 80%). ¹ H-NMR (DMSO- d ₆ , 300 MHz) δ 7.49 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 3.43 (m, 2H), 2.99 (m, 2H ), 2.97 (s, 3 H).

Step d: 4,4,5,5-tetramethyl-2- (4- (2- (methylsulfonyl) ethyl) -phenyl) -1,3,2-dioxaborolane

4,4,5,5-tetramethyl-2- (4- (2- (methylsulfonyl) ethyl) phenyl) -1,3,2-dioxaborolan to 1-methyl-4- [4- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] sulfonyl-piperazine was prepared in the same manner as described above (Preparation AA).

CC. Tertiary butyl methyl (4- (4,4,5,5- tetramethyl- 1,3,2 -dioxaborolan -2-yl) benzyl) carbamate

Step a: tertiary butyl-4-bromobenzylcarbamate

Commercially available p -bromobenzylamine hydrochloride (1 g, 4 mmol) was treated with 10% aqueous NaOH (5 mL). To the clear solution was added (Boc) ₂ O (1.1 g, 4.9 mmol) dissolved in dioxane (10 mL). The mixture was stirred vigorously for 18 hours at room temperature. The obtained residue was concentrated, and suspended in water (20㎖), ethyl acetate (4 × 20㎖) extract, tertiary and dried Na ₂ SO _4, filtered, and concentrated to a white solid by-butyl-4 Bromobenzylcarbamate (1.23 g, 96%) was obtained. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.48 (d, J = 8.4 Hz, 2H), 7.40 (t, J = 6 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 4.07 (d, J = 6.3 Hz, 2H), 1.38 (s, 9H).

Step b: 3-tert-butyl-4-bromobenzyl (methyl) carbamate

In 60㎖ vial was dissolved tert-butyl-4-bromo-benzyl carbamate (1.25g, 4.37mmol) in DMF (12㎖). Ag ₂ O (4.0 g, 17 mmol) was added to the solution, followed by CH ₃ I (0.68 mL, 11 mmol). The mixture was stirred at 50 ° C. for 18 h. The reaction mixture was filtered through celite and the celite was washed with methanol (2 × 20 mL) and dichloromethane (2 × 20 mL). The filtrate was concentrated to remove most of the DMF. The residue is treated with water (50 mL) and a white emulsion is formed. The mixture was extracted with ethyl acetate (4 × 25 mL), dried over Na ₂ SO ₄ and the solvent was evaporated to give tert butyl-4-bromobenzyl (methyl) carbamate (1.3 g, 98%) yellow Obtained as an oil. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.53 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 4.32 (s, 2H), 2.74 (s, 3H) , 1.38 (s, 9 H).

Step c: tertiary butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylmethylcarbamate

1-Methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] sulfonyl-piperazine (prepared AA) The coupling reaction was achieved in the same manner as described. After the coupling reaction, the crude reaction mixture was treated with 0.5 ml of 1N HCl in diethyl ether for 18 hours to remove the Boc protecting group and then purified by HPLC.

Except for using the aryl boronic acid set forth in Table 4, further examples of the present invention were prepared according to the above process without making any substantial changes.

(a) The crude reaction mixture was treated with 0.5 ml of 1N HCl in diethyl ether for 18 hours to remove the Boc protecting group after coupling reaction and then purified by HPLC.

Additional embodiments of the invention can be made by modifying the intermediates described above.

Compound after coupling Derivatization :

DD. 1- ( benzo [d] [1,3] dioxol -5-yl) -N- (6- (4- (2 -methylpyrrolidin- 1- ylsulfonyl ) phenyl ) pyridin-2-yl) cyclo Propanecarboxamide

Step a: 4- (4,4'-dimethoxybenzhydryl) -thiophenyl boronic acid

4,4'-dimethoxybenzhydrol (2.7g, 11mmol) and 4-mercaptophenylboronic acid (1.54g, 10mmol) were dissolved in 20ml of AcOH and heated at 60 ° C for 1 hour. The solvent was evaporated and the residue dried under high vacuum. The material was used without further purification.

Step b: 6- (4- (bis (4-methoxyphenyl) methylthio) phenyl) pyridin-2-amine

4- (4,4'-dimethoxybenzhydryl) -thiophenyl boronic acid (10 mmol) and 2-amino-6-bromopyridine (1.73 g, 10 mmol) were dissolved in MeCN (40 mL), followed by Pd (PPh ₃ ) ₄ (˜50 mg) and aqueous K ₂ CO ₃ (1M, 22 mL) were added. The reaction mixture was partitioned and heated in a microwave oven (160 ° C., 400 seconds). The product was partitioned between ethyl acetate and water. The organic layer was washed with water, brine and dried over MgSO ₄ . The volatiles were evaporated to give an oil which was used in the next step without further purification. ESI-MS m / z calc. 428.0. Found 429.1 (M + 1).

Step c: 1- (benzo [d] [1,3] dioxol-5-yl) - N - (6- (4- (bis (4-methoxyphenyl) methyl) phenyl) -pyridin-2 (1) cyclopropanecarboxamide

6-[(4,4'-dimethoxybenzhydryl) -4-thiophenyl] pyridin-2-ylamine (~ 10 mmol) and 1-benzo [1,3] dioxol-5-yl-cyclopropanecarboxylic acid (2.28 g, 11 mmol) was dissolved in chloroform (25 mL), then TCPH (4.1 g, 12 mmol) and DIEA (5 mL, 30 mmol) were added. The reaction mixture was heated at 65 ° C. for 48 hours, after which the volatiles were removed under reduced pressure. The residue was transferred to a separatory funnel and partitioned between water (200 mL) and ethyl acetate (150 mL). The organic layer was washed with 5% NaHCO ₃ (2 × 150 mL), water (1 × 150 mL), brine (1 × 150 mL) and dried over MgSO ₄ . Evaporation of the solvent crude l- (benzo [d] [1,3] dioxol-5-yl) - N - (6- (4- (bis (4-methoxyphenyl) methyl) phenyl) pyridin- 2-yl) cyclopropanecarboxamide was obtained as a pale oil. ESI-MS m / z calc. 616.0, found 617.0 (M + 1) (HPLC purity -85%, UV254 nm).

Step d: 4- (6- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropane-carboxamido) pyridin-2-yl) benzenesulfonic acid

1- (benzo [d] [1,3] dioxol-5-yl) - N - (6- (4- (bis (4-methoxyphenyl) methylthio) phenyl) pyridin-2-yl) cyclopropanecarboxylate Propanecarboxamide (˜8.5 mmol) was dissolved in AcOH (75 mL), then 30% H ₂ O ₂ (10 mL) was added. Additional hydrogen peroxide (10 mL) was added after 2 hours. The reaction mixture was stirred at 35-45 ° C. overnight (˜90% conversion, HPLC). The volume of the reaction mixture was reduced to one third by evaporation (bath temperature below 40 ° C.). The reaction mixture was weighted directly to the preparative HPLC column (C-18) and purified. Fractions with 4- (6- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) pyridin-2-yl) benzenesulfonic acid were recovered and evaporated (1.9 g, 43%, calculated on the basis of 4-mercapto-phenylboronic acid). ESI-MS m / z calc. 438.0. Found 438.9 (M + 1).

Step e: 4- (6- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropane-carboxamido) pyridin-2-yl) benzene-1-sulfonyl chloride

4- (6- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) pyridin-2-yl) benzenesulfonic acid (1.9 g, 4.3 mmol) was dissolved in POCl ₃ (30 mL), then SOCl ₂ (3 mL) and DMF (100 μL) were added. The reaction mixture was heated at 70-80 ° C. for 15 minutes. The volatiles were evaporated and then evaporated again with chloroform-toluene. The remaining brown oil was diluted with chloroform (22 mL) and used immediately for sulfonylation. ESI-MS m / z calc. 456.0. Found 457.1 (M + 1).

Step f: 1- (benzo [d] [1,3] dioxol-5-yl) - N - (6- (4- (2- methyl-pyrrolidin-1-some accounts) phenyl) pyridin-2- (1) cyclopropanecarboxamide

4- (6- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) pyridin-2-yl) benzene-1-sulfonyl chloride (~ 35 μmol, chloroform Solution in 400 μl) was treated with 2-methylpyrrolidine and then DIEA (100 μl) was added. The reaction mixture was kept at rt for 1 h, concentrated and diluted with DMSO (400 μl). The resulting solution was treated by HPLC purification. Fractions containing the desired material were combined and concentrated at 40 ° C. in a vacuum centrifuge to give the trifluoroacetic acid salt of the target material (ESI-MS m / z calc. 505.0, found 505.9 (M + 1), retention time 4.06 min). ¹ H NMR (250 MHz, DMSO- d ₆ ) δ 1.15 (m. 2H), δ 1.22 (d, 3H, J = 6.3 Hz), δ 1.41-1.47 (m, 2H), δ 1.51 (m, 2H) , δ 1.52-1.59 (m, 2H), δ 3.12 (m, 1H), δ 3.33 (m, 1H), δ 3.64 (m, 1H), δ 6.07 (s, 2H), δ 6.96-7.06 (m, 2H), δ 7.13 (d, 1H, J = 1.3 Hz), δ 7.78 (d, 1H, J = 8.2 Hz), δ 7.88 (d, 2H, J = 8.5 Hz), δ 7.94 (t, 1H, J = 8.2 Hz), δ 8.08 (d, 1H, J = 8.2 Hz), δ 8.16 (d, 2H, J = 8.5 Hz), δ 8.53 (s, 1H).

The compounds in the following table were synthesized as described above using commercially available amines. Further examples of the present invention were made according to the above process with virtually no change except using the amines shown in Table 5.

EE. 1- Benzo [1,3] dioxol -5-yl- N- [6- [4-[( methyl - methylsulfonyl -amino) methyl ] phenyl ] -2 -pyridyl ] -cyclopropane-1- car Voxamide ( Compound No. 292)

Dichloroethane (DCE) (1.5 mL) was added to the starting amine (brown semi-solid, 0.100 g, ˜0.2 mmol, obtained by treatment with the corresponding t -butyloxycarbonyl derivative in 1N HCl in ether) followed by pyridine (0.063 mL, 0.78 mmol) and methanesulfonyl chloride (0.03 mL, 0.4 mmol) were added. The mixture was stirred at 65 ° C. for 3 hours. LC / MS analysis then showed 50% conversion to the desired product. Additional 2 equivalents of pyridine and 1.5 equivalents of methanesulfonyl chloride were added and the reaction stirred for 2 hours. The residue was concentrated and purified by HPLC to give 1-benzo [1,3] dioxol-5-yl- N- [6- [4-[(methyl-methylsulfonyl-amino) methyl] phenyl] -2-pyri Dill] -cyclopropane-1-carboxamide (0.020 g, 21% yield) was obtained as a white solid. ESI-MS m / z calc. 479.2. Found 480.1 (M + 1) ⁺ .

FF. (R) -1- (3- hydroxy-4-methoxyphenyl) - N - (6- (4- (2- ( hydroxymethyl) -pyrrolidine-l-some accounts) phenyl) pyridin-2 - yl) cyclopropane carboxamide

(R) -1- (3- (benzyloxy) -4-methoxyphenyl) - N - (6- (4- (2- ( hydroxymethyl) pyrrolidin-1-some accounts) phenyl) pyridin- 2-yl) cyclopropanecarboxamide (28 mg, 0.046 mmol) was dissolved in ethanol (3 mL). Palladium on charcoal (10%, 20 mg) was added and the reaction was stirred overnight under 1 atmosphere of hydrogen. The catalyst was filtered off, the product was separated by silica gel chromatography (50-80% EtOAc in hexane) to (R) -1- (3- hydroxy-4-methoxyphenyl) - N - (6- (4- (2- (hydroxymethyl) pyrrolidin-1-ylsulfonyl) phenyl) pyridin-2-yl) cyclopropanecarboxamide (8 mg, 34%) was provided. ESI-MS m / z calc. 523.4, found 524.3 (M + 1) ⁺ . Retention time 3.17 minutes.

2-amino-5-phenylpyridine (CAS [33421-40-8]) is C-1.

GG. ( R )-(1- (4- (6 -aminopyridin - 2 -yl) phenylsulfonyl ) pyrrolidin- 2 - yl) methanol hydrochloride (C-2)

Step a: ( R )-(1- (4-bromophenylsulfonyl) pyrrolidin-2-yl) methanol

4-bromine in CH ₂ Cl ₂ (100 mL) in a mixture of saturated aqueous NaHCO ₃ (44 g, 0.53 mol), CH ₂ Cl ₂ (400 mL) and pyrrolidin-2-yl-methanol (53 g, 0.53 mol) A solution of parent benzenesulfonyl chloride (127 g, 0.50 mol) was added. The reaction was stirred at 20 ° C. overnight. The organic phase was separated and dried over Na ₂ SO ₄ . Evaporation of the solvent under reduced pressure yields ( R )-(1- (4-bromophenylsulfonyl) pyrrolidin-2-yl) methanol (145 g, crude product), which is obtained in the next step without further purification. Used. ¹ H NMR (CDCl _{3 ,} 300 MHz) δ 7.66-7.73 (m, 4H), 3.59-3.71 (m, 3H), 3.43-3.51 (m, 1H), 3.18-3.26 (m, 1H) , 1.680-1.88 (m, 3H), 1.45-1.53 (m, 1H).

Step b: ( R ) -1- (4-Bromo-benzenesulfonyl) -2- ( tertiary butyl-dimethyl-silanyloxymethyl) pyrrolidine

[1- (4-Bromo-benzenesulfonyl) -pyrrolidin-2-yl] -methanol (50.0 g, 0.16 mol) and 1H-imidazole (21.3 g, 0.31 in CH ₂ Cl ₂ (500 mL) mol) to tertiary butylchlorodimethylsilane (35.5 g, 0.24 mol) was added in portions. After addition, the mixture was stirred at rt for 1 h. The reaction was quenched with water (200 mL) and the separated aqueous layer was extracted with CH ₂ Cl ₂ (100 mL × 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , and evaporated under vacuum to afford 1- (4-bromo-benzenesulfonyl) -2- ( tert- butyldimethylsilanyloxymethyl) pyrrolidine ( 68.0 g, 99%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.63-7.71 (m, 4 H), 3.77-3.81 (m, 1 H), 3.51-3.63 (m, 2 H), 3.37-3.43 (m, 1 H) , 3.02-3.07 (m, 1H), 1.77-1.91 (m, 2H), 1.49-1.57 (m, 2H), 0.87 (s, 9H), 0.06 (d, J = 1.8 Hz, 6H ).

Step c: (R) -4- (2 - ((3 -tert-butyldimethylsilyloxy) methyl) pyrrolidin-1-some accounts) phenyl boronic acid

1- (4-Bromo-benzenesulfonyl) -2- ( tert butyl-dimethyl-silanyloxymethyl) pyrrolidine (12.9 g, 29.7 mmol) and B (O ⁱ Pr in dry THF (100 mL) To a solution of) ₃ (8.4 g, 45 mmol) was added dropwise n- BuLi (2.5M in hexane, 29.7 mL) at -70 ° C. After dropping, the mixture was slowly warmed to −10 ° C. and treated with HCl (1M, 50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na ₂ S0 ₄ and evaporated in vacuo. The combined organics were crude (R) -4- (2 - ( (3 -tert-butyldimethylsilyloxy) methyl) pyrrolidin-1-sulfonyl some accounts) to give the boronic acid (15.0g), and used directly in the next step It was.

Step d: (6- {4- [2- ( tertiary butyl-dimethyl-silanyloxymethyl) -pyrrolidine-1-sulfonyl] phenyl} pyridin-2-yl) carbamic acid tertiary butyl ester

DMF (250㎖) of (6-bromo-pyridin-2-yl) carbamic acid tert-butyl ester To a solution of (24.6g, 90.0mmol), (R) -4- (2 - ((tert-butyldimethylsilyl Oxy) -methyl) pyrrolidin-1-ylsulfonyl) phenylboronic acid (45.0 g), Pd (PPh ₃ ) ₄ (10.4 g, 9.0 mmol), potassium carbonate (18.6 g, 135 mol) and water (200 mL) Was added. The resulting mixture was degassed by slightly bubbling argon through the solution at 20 ° C. for 5 minutes. The reaction mixture was then heated at 80 ° C. overnight. The DMF was removed under vacuum. EtOAc (300 mL) was added to the residue. The mixture was filtered through a pad of silica gel, which was washed with EtOAc (50 mL × 3). The combined organic extracts were evaporated in vacuo. The crude residue was purified by column (petroleum ether / EtOAc 20: 1) to give (6- {4- [2- ( tert butyl-dimethyl-silanyloxymethyl) pyrrolidine-1-sulfonyl] phenyl} pyridine- 2-yl) carbamic acid tertiary butyl ester (22.2 g, 45% for two steps) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.09 (d, J = 8.4 Hz, 2H), 7.88-7.96 (m, 3H), 8.09 (t, J = 7.8 Hz, 1H), 7.43-7.46 (m, 1H), 7.38 (s, 1H), 3.83-3.88 (m, 1H), 3.64-3.67 (m, 1H), 3.53-3.59 (m, 1H), 3.41-3.47 (m , 1 H), 3.08-3.16 (m, 1 H), 1.82-1.91 (m, 2 H), 1.67-1.69 (m, 1 H), 1.53-1.56 (m, 10 H), 0.89 (s, 9 H), 0.08 (d, J = 2.4 Hz, 6 H).

Step e: {6- [4- (2-Hydroxymethyl-pyrrolidine-1-sulfonyl) -phenyl] pyridin-2-yl carbamic acid tertiary butyl ester

Crude (6- {4- [2- ( tert butyl-dimethyl-silanyloxymethyl) -pyrrolidine-1-sulfonyl] phenyl} -pyridin-2-yl) carbamic acid 3 in DCM (300 mL) A solution of tertiary butyl ester (22.2 g, 40.5 mmol) and TBAF (21.2 g, 81.0 mmol) was stirred overnight at room temperature. The mixture was washed with brine (100 mL × 3), dried over Na ₂ SO ₄ and evaporated in vacuo to afford {6- [4- (2-hydroxymethyl-pyrrolidine-1-sulfonyl) -phenyl] Pyridin-2-yl} carbamic acid tertiary butyl ester (15.0 g, 86%) was obtained and used directly in the next step.

Step f: ( R )-(1- (4- (6-aminopyridin-2-yl) phenylsulfonyl) -pyrrolidin-2-yl) methanolic hydrochloride (C-2)

{6- [4- (2-hydroxymethyl-pyrrolidine-1-sulfonyl) -phenyl] pyridin-2-yl} carbamic acid tertiary butyl ester in HCl / MeOH (50 mL, 2M) (15.0 g) , 34.6 mmol) was heated to reflux for 2 hours. After cooling to room temperature, the reaction mixture is evaporated in vacuo and washed with EtOAc ( R )-(1- (4- (6-aminopyridin-2-yl) phenylsulfonyl) pyrrolidin-2-yl) Methanol hydrochloride (C-2; 11.0 g, 86%) was obtained. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.18 (d, J = 8.7 Hz, 2 H), 7.93-7.99 (m, 3H), 7.31 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 3.53-3.57 (m, 2H), 3.29-35 (m, 2H), 3.05-3.13 (m, 1H), 1.77-1.78 (m, 2H ), 1.40-1.45 (m, 2H). MS (ESI) m / z (M + H) ⁺ 334.2.

HH. N- (4- (6 -aminopyridin - 2 -yl) benzyl) methanesulfonamide (C-3)

Step a: [6- (4-cyano-phenyl) -pyridin-2-yl] carbamic acid tertiary butyl ester

4-cyanobenzeneboronic acid (7.35 g, 50 mmol) in DMF / H ₂ O (1: 1, 250 mL), (6-bromo-pyridin-2-yl) carbamic acid tertiary butyl ester (13.8 g, 50 mmol), Pd (Ph ₃ P) ₄ (5.8 g, 0.15 mmol) and K ₂ CO ₃ (10.4 g, 75 mmol) were stirred overnight at 80 ° C. under argon. DMF was evaporated under reduced pressure and the residue was dissolved in EtOAc (200 mL). The mixture was washed with water and brine, dried over Na ₂ S0 ₄ and concentrated to dryness. The residue was purified by a column on silica gel (petroleum ether / EtOAc 50: 1) to give [6- (4-cyano-phenyl) -pyridin-2-yl] carbamic acid tertiary butyl ester (7.0 g, 60%). It was. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.02-8.07 (m, 2H), 7.95 (d, J = 8.4 Hz , 1H), 7.71-7.79 (m, 3H), 7.37-7.44 (m, 2 H), 1.53 (s, 9 H).

Step b: [6- (4-Aminomethyl-phenyl) -pyridin-2-yl] -carbamic acid tertiary butyl ester

[6- (4-cyano-phenyl) -pyridin-2-yl] carbamic acid tertiary butyl ester (7.0 g, 24 mmol), Raney Ni in EtOH (500 mL) and NH ₃ .H ₂ O (10 mL) (1.0 g) of the suspension was hydrogenated at 50 ° C. under H ₂ (50 psi.) For 6 hours. The catalyst was filtered off and the filtrate was concentrated to dryness to afford [6- (4-aminomethyl-phenyl) -pyridin-2-yl] -carbamic acid tertiary butyl ester, which was used directly in the next step. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.83-7.92 (m, 3H), 7.70 (t, J = 7.8 Hz , 1 H), 7.33-7.40 (m, 4 H), 3.92 (brs, 2 H) , 1.53 (s, 9 H).

Step c: {6- [4- (Methanesulfonylamino-methyl) -phenyl] -pyridin-2-yl} carbamic acid tertiary butyl ester

To a solution of [6- (4-aminomethyl-phenyl) -pyridin-2-yl] -carbamic acid tertiary butyl ester (5.7 g 19 mmol) and Et ₃ N (2.88 g, 29 mmol) in dichloromethane (50 mL) MsCl (2.7 g, 19 mmol) was added dropwise at 0 ° C. The reaction mixture was stirred at this temperature for 30 minutes, then washed with water and brine, dried over Na ₂ S0 ₄ and concentrated to dryness. The residue was recrystallized from DCM / petroleum ether (1: 3) to give {6- [4- (methanesulfonylamino-methyl) -phenyl] -pyridin-2-yl} carbamic acid tertiary butyl ester (4.0 g, two 44%) for the step). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.90-7.97 (m, 3H), 7.75 (t, J = 8.4, 8.4 Hz, 1H), 7.54-7.59 (m, 1H), 7.38-7.44 ( m, 3H), 4.73 (br, 1H), 4.37 (d, J = 6.0 Hz, 2H), 2.90 (s, 3H), 1.54 (s, 9H).

Step d: N- (4- (6-Aminopyridin-2-yl) benzyl) methane-sulfonamide (C-3)

A mixture of {6- [4- (methanesulfonylamino-methyl) -phenyl] -pyridin-2-yl} carbamic acid tertiary butyl ester (11 g, 29 mmol) in HCl / MeOH (4M, 300 mL) at room temperature Stir overnight. The mixture was concentrated to dryness. The residue was filtered and washed with ether to give N- (4- (6-aminopyridin-2-yl) benzyl) methane sulfonamide (C-3) (7.6 g, 80%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 14.05 (br s, 1 H), 8.24 (br s, 2 H), 7.91-7.98 (m, 3H), 7.70 (t, J = 6.0 Hz, 1 H), 7.53 (d, J = 8.1 Hz, 2 H), 7.22 (d, J = 6.9 Hz, 1 H), 6.96 (d, J = 9 Hz, 1 H), 4.23 (d, J = 5.7 Hz, 2H), 2.89 (s, 3H). MS (ESI) m / z (M + H) ⁺ : 278.0,

II. 4- (6- Aminopyridin- 2-yl) -N - methylbenzenesulfonamide Hydrochloride (C-4)

Step a: 4-bromo- N -methyl-benzenesulfonamide

4-bromo in CH ₂ Cl ₂ (100 mL) in a mixture of saturated aqueous NaHCO ₃ (42 g, 0.5 mol), CH ₂ Cl ₂ (400 mL) and methylamine (51.7 g, 0.5 mol, 30% in methanol) A solution of benzenesulfonyl chloride (127 g, 0.5 mol) was added. The reaction was stirred at 20 ° C. overnight. The organic phase was separated and dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure to afford 4-bromo- N -methyl-benzenesulfonamide (121 g, crude product) which was used in the next step without further purification. ¹ H NMR (CDCl _{3 ,} 300 MHz) δ 7.64-7.74 (m, 4H), 4.62-4.78 (m, 1H), 2.65 (d, J = 5.4 Hz, 3H).

Step b: 4- ( N -methylsulfamoyl) phenylboronic acid

N -BuLi at −70 ° C. in a solution of 4-bromo- N -methyl-benzene sulfonamide (24.9 g, 0.1 mol) and B (O ⁱ Pr) ₃ (28.2 g, 0.15 mol) in THF (200 mL) (100 mL, 0.25 mol) was added. The mixture was slowly warmed to 0 ° C., then 10% HCl solution was added to pH 3-4. The resulting mixture was extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ and evaporated under reduced pressure to afford 4- ( N -methylsulfamoyl) phenylboronic acid (22.5 g, 96%) which was used in the next step without further purification. ¹ H NMR (DMSO- d ₆ , 300 MHz) δ 8.29 (s, 2H), 7.92 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 2.36 (d , J = 5.1 Hz, 3 H).

Step c: 3-tert-butyl 6- (4- (N - methyl sulfamoyl) phenyl) pyridin-2-yl carbamate

4- ( N -methylsulfamoyl) phenylboronic acid (17.2 g, 0.08 mol) and (6-bromo-pyridin-2-yl) carbamic acid tertiary in DMF (125 mL) and H ₂ O (125 mL) To a solution of butyl ester (21.9 g, 0.08 mol) was added Pd (PPh ₃ ) ₄ (9.2 g, 0.008 mol) and K ₂ CO ₃ (16.6 g, 0.12 mol). The resulting mixture was degassed by lightly bubbling argon through the solution at 20 ° C. for 5 minutes. The reaction mixture was then heated at 80 ° C. for 16 hours. The mixture was evaporated under reduced pressure, then poured into H ₂ O and extracted with EtOAc. The organic phase was dried over Na ₂ SO ₄ and evaporated under reduced pressure to afford tert- butyl 6- (4- ( N -methylsulfamoyl) phenyl) pyridin-2-ylcarbamate (21 g, 58%). Used in the next step without further purification.

Step d: 4- (6-Aminopyridin-2-yl) -N -methylbenzenesulfonamide hydrochloride

To a solution of tert- butyl 6- (4- ( N -methylsulfamoyl) phenyl) pyridin-2-ylcarbamate (8.5 g, 23.4 mmol) in MeOH (10 mL) at room temperature in HCl / MeOH (2M, 50 mL) ) Was added. The suspension was stirred overnight at room temperature. The solid product was recovered by filtration, washed with MeOH and dried to afford 4- (6-aminopyridin-2-yl) -N -methylbenzenesulfonamide hydrochloride (5.0 g, 71%). ¹ H NMR (300 Hz, DMSO- d ₆ ) δ 8.12 (d, J = 8.4 Hz, 2 H), 7.91-7.96 (m, 3H), 7.58-7.66 (m, 1H), 7.31-7.53 ( m, 1H), 7.27 (d, J = 6.6, 1H), 6.97 (d, J = 9.0, 1H), 2.43 (d, J = 4.8 Hz, 3H). MS (ESI) m / z (M + H) ⁺ 264.0.

The compounds in the following table were either commercially available or synthesized as described above using the carboxylic acids and amines described above.

Physical data for an embodiment of the present invention is shown in Table 7.

Additional Exemplary Compounds 164-388, shown in Table 1, may also be prepared using suitable starting materials and methods exemplified for the compounds described above.

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ΔF508- of compounds CFTR  Test for detection and measurement of calibration characteristics

JJ. Membrane Potential Optical Method to Assay ΔF508- CFTR Modulating Properties of Compounds

Optical film potential assays can be used in fluorescence change measurement instruments such as voltage / iron probe readers (VIPR) [Gonzalez, J. E., K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4 (9): 431-439], Gonzalez, JE and RY Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells "Biophys J 69 (4): 1272-80, and Gonzalez, JE and RY Tsien (1997)" Improved indicators of cell membrane potential that use fluorescence resonance energy transfer "Chem Biol 4 (4): 269- 77] was used for the voltage sensitive FRET sensor.

This voltage sensitive assay is based on the change in fluorescence resonance energy transfer (FRET) between the membrane solubility, the voltage sensitive dye DiSBAC ₂ (3) and the fluorescent phospholipid CC2-DMPE (which attaches to the outer leaflet of the plasma membrane and acts as a FTET donor). Shall be. The change in membrane potential (V _m ) redistributes negatively charged DiSBAC ₂ (3) across the plasma membrane and causes the amount of energy transfer from CC2-DMPE to change. Changes in fluorescence emission were monitored using VIPR ^™ II, an integrated liquid handler and fluorescence detector designed to perform cell-based screens in 96-well or 384-well microtiter plates.

1. Identification of Calibration Compound

To identify small molecules that correct for trafficking defects associated with ΔF508-CFTR, a single-added HTS assay format was developed. Cells were cultured in serum-free medium for 16 hours at 37 ° C. in the presence or absence of a test compound (negative control). As a positive control, cells plated in 384-well plates were incubated for 16 hours at 27 ° C. to “temperature-correct” ΔF508-CFTR. Cells were then washed three times with solutions (Krebs Ringers) and loaded with voltage sensitive dye. To activate ΔF508-CFTR, 10 μM forskolin and CFTR potentiator, Genistein (20 μM) were added to each well with Cl ⁻ free medium. The addition of Cl ⁻ free medium enhanced Cl ⁻ efflux in response to ΔF508-CFTR activation, and the resulting membrane depolarization was optically monitored using FRET-based voltage-sensor dyes.

2. Potentiator  Identification of compounds

To identify potentiators of ΔF508-CFTR, a dual-added HTS assay format was developed. Cl ⁻ free medium was added to each well in the presence or absence of the test compound during the first addition. After 22 seconds, a second addition of Cl ⁻ free medium containing 2-10 μM forskolin was added to activate ΔF508-CFTR. After the addition the extracellular Cl ⁻ concentration was 28 mM, which enhanced Cl ⁻ efflux in response to ΔF508-CFTR activation, and the resulting membrane depolarization was optically monitored using a FRET-based voltage-sensor dye It was.

3. Solution

Bath # 1: (mM) NaCl 160, KCl 4.5, CaCl ₂ 2, MgCl ₂ 1, HEPES 10, pH 7.4 (using NaOH).

Chloride-free bath: Substitute the chloride salt in bath # 1 with the gluconate salt.

CC2-DMPE: Prepared as 10 mM stock solution in DMSO and stored at -20 ° C.

DiSBAC ₂ (3): Prepared as ₁₀ mM stock in DMSO and stored at -20 ° C.

4. Cell Culture

NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR were used for optical measurement of membrane potential. Cells were harvested in 5% CO in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 × NEAA, β-ME, 1 × pen / strep and 25 mM HEPES in 175 cm 2 culture flasks. _It was kept at 37 ° C. under ₂ and 90% humidity. For all optical assays, cells were seeded at 30,000 / well in 384-well Matrigel-coated plates, incubated at 37 ° C. for 2 hours and then at 27 ° C. for 24 hours for potentiator assays. For calibration assays, cells were cultured at 27 ° C. or 37 ° C. in the presence or absence of compounds for 16 to 24 hours.

ΔF508- of compounds CPTR  Electrophysiological Assays to Test Regulatory Properties

One. Youssing ( Ussing ) chamber  black

The chamber experiments identified in the optical assays were performed for use chamber experiments on polarized epithelial cells expressing ΔF508-CFTR to further characterize the ΔF508-CFTR modulator. FRT ^ΔF508-CFTR epithelial cells grown in a Costar Snapwell cell culture insert are placed in a Physiologic Instruments, Inc., San Diego, Calif., And a Voltage-clamp System: Department of Bioengineering Monolayers were continuously short-circulated using the University of Iowa, IA, and, Physiologic Instruments, Inc., San Diego, Calif. Transdermal resistance was measured by applying a 2-mV pulse. Under these conditions, the FRT epithelium showed a resistance of at least 4 KΩ / CM ² . This solution was kept at 27 ° C. and bubbled with air. Electrode offset potential and fluid resistance were calibrated using cell free inserts. Under these conditions, the current reflects the flow of Cl ⁻ through ΔF508-CFTR expressed in the tip membrane. MP100A-CE interface and AcqKnowledge software; using (v3.2.6 BIOPAC Systems, Santa Barbara, CA) was obtained by digitizing the I _sc.

2. Identification of Correction Compounds

The basal side was used for the apical Cl ⁻ concentration gradient according to a conventional protocol. To establish this gradient, normal Ringer was used for the basal membrane and the peak NaCl was replaced with an equimolar amount of sodium gluconate (titrated to pH 7.4 with NaOH) to create a large Cl ⁻ concentration gradient across the epithelium. All experiments were performed in intact monolayers. To fully activate ΔF508-CFTR, forskolin (10 μM) and the PDE inhibitor IBMX (100 μM) were added and a CFTR potentiator, Genistein (50 μM) was added.

As observed in other cell types, culturing at low temperatures of FRT cells stably expressing ΔF508-CFTR increases the functional density of CFTR in the plasma membrane. To determine the activity of the calibration compounds, cells were incubated with 10 μM test compound for 24 hours at 37 ° C. and washed three times before recording. Normalized to the cAMP- and Jenny stay mediated I _sc in the compound treated cells to 27 ℃ and 37 ℃ control group, and was expressed as% activity. Preincubation of the cells with the calibrating compound resulted in a significant increase in cAMP- and Zenithtay mediated I _sc compared to the 37 ° C. control.

3. Potentiator  Identification of compounds

The basal side was used for the apical Cl ⁻ concentration gradient according to a conventional protocol. To establish this gradient, use normal Ringer on the basal membrane, allow permeation with nistatin (360 μg / ml), and replace the peak NaCl with an equimolar amount of sodium gluconate (titrated to pH 7.4 with NaOH). A large Cl ^- concentration gradient was made across the epithelium. All experiments were performed 30 minutes after nystatin permeation. Forskolin (10 μM) and all test compounds were added to both sides of the cell culture insert. The efficacy of the putative ΔF508-CFTR potentiator was compared with the efficacy of the known potency genistein.

4. Solution

Base solution (mM): NaCl (135), CaCl ₂ (1.2), MgCl ₂ (1.2), K ₂ HPO ₄ (2.4), KHPO ₄ (0.6), N-2-hydroxyethylpiperazine-N ' 2-ethanesulfonic acid (HEPES) (10), and dextrose (10). The solution was titrated with NaOH to pH 7.4.

Peak Solution (mM): Same as Base Solution, except NaCl is replaced with Na Gluconate 135.

5. Cell Culture

Fisher rat epithelial (FRT) cells expressing ΔF508-CFTR (FRT ^ΔF509-CFTR ) were used in the use chamber test for the putative ΔF508-CFTR modulator identified from the optical assay. Cells were cultured on Costa Snapwell cell culture inserts and 37 ° C. in Coon's modified Ham's F-12 medium supplemented with 5% fetal calf serum, 100 U / ml penicillin and 100 μg / ml streptomycin. And incubated for 5 days under 5% CO ₂ . Prior to use to characterize the potentiator activity of the compounds, cells were incubated at 27 ° C. for 16-48 hours to correct for ΔF508-CFTR. To measure the activity of the calibration compounds, cells were incubated at 27 ° C. or 37 ° C. for 24 hours with or without compounds.

6. Complete cell record

Macroscopic ΔF508-CFTR currents (I _ΔF508 ) in temperature- and test compound-calibrated NIH3T3 cells stably expressing ΔF508-CFTR were monitored using a puncture-patch, whole cell record. Briefly, voltage-clamp _recording of I _ΔF508 was performed at room temperature using an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc., Foster City, Calif.). All records were obtained at a sampling frequency of 10 kHz and low pass filtered at 1 kHz. The pipette showed a resistance of 5-6 MΩ when charged with intracellular solution. Under these recording conditions, the calculated reverse potential for Cl ⁻ (E _cl ) at room temperature was −28 mV. All records had a seal resistance of more than 20 GΩ and a series resistance of less than 15 MΩ. Pulse generation, data accumulation and analysis were performed using a PC with Digidata 1320 A / D interface with Clampex 8 (Axon Instruments Inc.). The bath contained less than 250 μl of saline and was continuously perfused at a rate of 2 ml / min using a gravity-driven perfusion system.

7. Identification of Calibration Compound

To measure the activity of the calibration compound to increase the density of functional ΔF508-CFTR in the plasma membrane, we measured the current density after 24 hours of treatment with the calibration compound using the above-described puncture patch recording technique. To fully activate ΔF508-CFTR, 10 μM Forskolin and 20 μM Genistein were added to the cells. Under our recording conditions, the current density after 24 hours incubation at 27 ° C. was higher than the current density observed after 24 hours incubation at 37 ° C. This result is consistent with the known effect of cold culture on the density of ΔF508-CFTR in the plasma membrane. To determine the effect of the calibration compound on CFTR current density, cells were incubated with 10 μM test compound for 24 hours at 37 ° C. and current densities were compared with 27 ° C. and 37 ° C. controls (% active). Prior to recording, cells were washed three times with extracellular recording medium to remove residual test compounds. Preincubation with 10 μM calibrated compound resulted in a significant increase in cAMP- and genistein dependent current compared to the 37 ° C. control.

8. Potentiator  Identification of compounds

The ability of the ΔF508-CFTR _potentiator to increase the macroscopic ΔF508-CFTR Cl ⁻ current (I _ΔF508 ) in NIH3T3 cells stably expressing ΔF508-CFTR was investigated using a puncture patch recording technique. Potentiators identified from the optical assays increased I _ΔF5O8 dose-dependently with similar efficacy and efficiency as observed in the optical assays. In all the cells examined, the reverse potential was about -30 mV (calculated E _Cl : -28 mV) before and during the application of the potentiator.

9. Solution

Intracellular solution (mM): Cs-aspartate (90), CsCl (50), MgCl ₂ (1), HEPES (10) and 240 μg / ml amphotericin-B (pH 7.35: adjusted with CsOH).

Extracellular solution (mM): N-methyl-D-glucamine (NMDG) -Cl (150), MgCl ₂ (2), CaCl ₂ (2), HEPES (10) (pH 7.35: adjusted with HCl).

10. Cell Culture

NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR were used for whole cell recording. Cells were harvested under 5% CO ₂ and 90% humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 × NEAA, β-ME, 1 × pen / strep and 25 mM HEPES in 175 cm 3 culture flasks. It was kept at 37 ° C. For total cell recording, 2,500 to 5,000 cells were seeded in poly-L-lysine-coated glass coverslips and incubated for 24 to 48 hours at 27 ° C. before testing potentiator activity; Incubation was performed in the presence or absence of the calibration compound to determine the activity of the calibration agent at 37 ° C.

11. Single channel recording

The single-channel activity of the temperature-corrected ΔF508-CFTR and potentiator compound activity, stably expressed in NIH3T3 cells, were observed using an incision-out membrane membrane patch. Briefly, voltage-clamp recording of single-channel activity was performed at room temperature using an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc.). All records were taken at a sampling frequency of 10 kHz and a low pass filtered at 400 Hz. Patch pipettes were made from Corning Kovar Sealing # 7052 glass (World Precision Instruments, Inc., Sarasota, FL) and had a resistance of 5-8 MΩ when charged with extracellular solution. After incision, 1 mM Mg-ATP, and 75 nM cAMP dependent protein kinase, catalytic subunit (PKA; Promega Corp. Madison, Wis.) Were added to activate ΔF508-CFTR. After stabilizing channel activity, the patches were perfused using a gravity-driven microperfusion system. The influent was placed adjacent to the patch to completely exchange the solution in 1-2 seconds. To maintain ΔF508-CFTR activity during rapid perfusion, nonspecific phosphatase inhibitor F ⁻ (10 mM NaF) was added to the bath. Under these recording conditions, channel activity remained constant throughout the patch recording (up to 60 minutes). The current generated by the positive charge (anion transfer in the opposite direction) from the intracellular solution to the extracellular solution is represented by a positive current. Pipette potential (V _p ) was maintained at 80 mV.

Channel activity was analyzed from membrane patches containing up to two active channels. The maximum number of simultaneous openings determined the number of active channels during the course of the experiment. To measure single-channel current magnitude, data recorded from 120 seconds of ΔF508-CFTR activity was “off-line” filtered at 100 Hz and multi-Gaussian using Bio-Patch Analysis software (Bio-Logic Comp. France). The full-point size histogram is fitted to the (multigaussian) function. Total micro current and Po (open probability) were measured from 120 seconds of channel activity. Po was determined using the Bio-Patch software or from the relation Po = I / i (N) [I: average current, i: single-channel current magnitude, N: number of active channels in the patch].

12. Solution

Extracellular solution (mM): NMDG (150), Aspartic Acid (150), CaCl ₂ (5), MgCl ₂ (2) and HEPES (10) (pH 7.35: adjusted with Tris base).

Intracellular solution (mM): NMDG-Cl (150), MgCl ₂ (2), EGTA (5), TES (10) and Tris base (14) (pH 7.35: adjusted with HCl).

13. Cell Culture

NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR were used for incision-membrane patch-clamp recordings. Cells were harvested under 5% CO ₂ and 90% humidity in Dulbecco's Modified Eagle's Medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 × NEAA, β-ME, 1 × pen / strep and 25 mM HEPES in 175 cm 2 culture flasks. It was kept at 37 ° C. For single channel recording, 2,500 to 5,000 cells were seeded on poly-L-lysine-coated coverslips and incubated for 24 to 48 hours at 27 ° C. prior to use.

The illustrated compounds of Table 1 have an activity in the range of about 100 nM to 20 mM, as measured using the assay described above. The illustrated compounds of Table 1 are found to be sufficiently effective as measured using the assays described above.

Other modes

While the present invention has been described in connection with the detailed description thereof, it is to be understood that the foregoing description is intended to illustrate the invention and not to limit the scope of the invention, which is limited by the appended claims. Other aspects, advantages and modifications fall within the scope of the following claims.

Claims (69)

The following compounds or pharmaceutically acceptable salts thereof.

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